T2-relaxation-under-spin-tagging Research Articles

Empirical model of human blood transverse relaxation at 3 T improves MRI T2 oximetry.

We sought a human blood T2 -oximetery calibration curve over the wide range of hematocrits commonly found in anemic patients applicable with T2 relaxation under spin tagging (TRUST). Blood was drawn from five healthy control subjects. Ninety-three in vitro blood transverse relaxation (T2b ) measurements were performed at 37°C over a broad range of hematocrits (10-55%) and oxygen saturations (14-100%) at 3 Tesla (T). In vivo TRUST was performed on 35 healthy African American control subjects and 11 patients with chronic anemia syndromes. 1/T2 rose linearly with hematocrit (r2 = 0.96), for fully saturated blood. Upon desaturation, 1/T2 rose linearly with the square of the oxygen extraction, (1-Y)2 , and the slope was linearly proportional to hematocrit (r2 = 0.88). The resulting bilinear model between 1/T2 , (1-Y)2 , and hematocrit had a combined r2 of 0.96 and a coefficient of variation of 6.1%. Using the in vivo data, the bilinear model had significantly lower bias and variability than existing calibrations, particularly for low hematocrits. In vivo Bland Altman analysis demonstrated clinically relevant bias that was -6% (absolute saturation) for hematocrits near 30% and rose to + 6% for hematocrits near 45%. This work introduces a robust bilinear calibration model that should be used for MRI oximetry. Magn Reson Med 77:2364-2371, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Abstract WP417: Oxygen Extraction Fraction Measured With MRI is Reduced After Blood Transfusion in Adults With Sickle Cell Anemia

Introduction: Blood transfusion for primary stroke prevention is well established in children but not adults with sickle cell anemia (SCA). Secondary stroke prevention in young adults with SCA is generally accepted. However blood transfusion therapy does not prevent all infarcts and recurrent assessment of cerebral physiology is likely necessary to portend stroke risk. Hypothesis: Oxygen extraction fraction (OEF), which reflects the balance of oxygen consumed to oxygen delivered, can be evaluated routinely noninvasively in vivo using MRI and reduces following blood transfusion; if confirmed, routine MRI-based OEF screening could be applied to evaluate impact of blood transfusion and other therapies on tissue-level impairment. Methods: The noninvasive T 2 -relaxation-under-spin-tagging (TRUST)-MRI method (duration=1min12s) was applied in adults with SCA (n=5) and age and race-matched control (n=11) volunteers. SCA volunteers were scanned pre- and post-transfusion and controls at two time points to assess healthy OEF reproducibility and hypothesized changes after transfusion, respectively. OEF changes were contrasted with symptoms, vasculopathy, and perfusion. A Kruskal-Wallis test with two-sided p<0.05 was used to evaluate significant differences. Results: In adults with SCA, mean age 33±3 years (y) OEF was significantly elevated (p<0.01, OEF=0.53±0.09) relative to controls (mean age 27±5y, OEF=0.32±0.06). OEF was not significantly different at follow-up for controls (OEF=0.33±0.05), but was reduced (OEF=0.44±0.05; p=0.021) following transfusion in SCA volunteers (Figure). Reduction in OEF is inversely correlated with increase in hematocrit post-transfusion. Conclusion: Noninvasive MRI can quickly detect expected reductions in OEF after blood transfusion. Ongoing work is focused on understanding relationships between OEF, changes in symptomatology and stroke risk in SCA. OEF has been predictive of stroke risk in other patient groups.

Abstract TMP93: Elevated Oxygen Extraction Fraction Measured With Noninvasive MRI may be Discriminatory for Stroke Risk in Adults With Sickle Cell Anemia

Introduction: No screening procedures exist for evaluating stroke risk in adults with sickle cell anemia (SCA). Reduced oxygen carrying capacity is present in SCA, which may initially be compensated for by an increase in cerebral blood flow (CBF) and then by increased oxygen extraction fraction (OEF). Hypothesis: OEF and CBF can be measured noninvasively and reproducibly with MRI using clinically-available equipment in adults with SCA; elevated OEF provides added discriminatory capacity for clinical impairment relative to vasculopathy extent and CBF alone. Methods: Structural, CBF-weighted, and MRA imaging, together with a noninvasive OEF-weighted T 2 -relaxation-under-spin-tagging (TRUST)-MRI method was applied in SCA adults (n=26) and race and age-matched controls (n=11). A Kruskal-Wallis test was applied to evaluate mean differences between SCA and control parameters. Linear regression assessed how elevated OEF correlated with increasing clinical impairment defined by presence of infarct, vasculopathy, or use of regular blood transfusions for SCA. Results: OEF had high reproducibility within the same scan session, n=37 (ICC = 0.989). Whole-brain OEF and CBF were increased in SCA adults (OEF=0.46±0.08; CBF=52.4±8.3 ml/100g/min) versus controls (OEF=0.35±0.06; CBF=43.6±5.1 ml/100g/min). Hematocrit and OEF were inversely correlated (R 2 =0.72; p<0.01). Linear regression revealed a stronger relationship of OEF than CBF with clinical impairment. In SCA adults without impairment (n=12) CBF and OEF have an inverse relationship (R 2 =0.41; p=0.01, Fig. 1A) but with clinical impairment (infarct, vasculopathy or severe pain requiring regular transfusions, n=14) CBF and OEF become uncoupled (R 2 =0.08; p=0.16; Fig. 1B) as CBF may not be able to increase further and may plateau or decline. Conclusion: TRUST-MRI OEF is a rapid, reproducible measure. OEF shows promise as screening tool for hemodynamic impairment and stroke risk in adults with SCA.

Cerebral perfusion differences in women currently with and recovered from anorexia nervosa

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.

Elevated Cerebral Metabolic Oxygen Consumption in Sickle Cell Disease

Introduction Stroke occurs when cerebral blood flow (CBF) is inadequate to the metabolic needs of the brain. In sickle cell disease (SCD) stroke is common, however accurate quantification of basal cerebral oxygen consumption (CMRO2) has not been performed. Early PET studies suggested CMRO2 was decreased in SCD patients, but these studies lacked data regarding brain volume and gray-white matter fractions; lower CMRO2 may simply have reflected brain loss from prior stroke. In contrast, NIRS and global resting energy expenditure studies have demonstrated elevated peripheral metabolic rate in SCD patients at baseline, with further increases during painful crisis. In those studies, oxygen consumption was correlated with markers of inflammation, particularly white blood cell count, consistent with metabolic consequences of neutrophil activation. Characterizing CMRO2 in SCD provides insight into better prevention and management of stroke in the SCD population. Accordingly, we measured CBF and cerebral venous saturation (SvO2) via a recently developed magnetic resonance imaging (MRI) technique: T2 Relaxation Under Spin Tagging (TRUST). Using the Fick Principle, this allowed for quantification of oxygen extraction fraction (OEF) and the first quantitative measurements of CMRO2in SCD patients.Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Fifteen patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. TRUST was used to measured T2 relaxation of blood within the sagittal sinus; T2 relaxation was converted to SvO2 using established calibration curves. OEF represented the difference of SaO2 andSvO2 .Phase Contrast (PC) of the carotid and vertebral arteries was used to measure global CBF. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for grey-white segmentation and brain volume calculations using BrainSuiteñ software. Relative grey matter CMRO2 and white matterCMRO2 were estimated by assuming that (gm) CMRO2 was three-fold higher than (wm) CRMRO2. Complete blood count, cell free hemoglobin, LDH, and hemoglobin electrophoresis were measured at the study visit.Results Table 1 summarizes the results. To compensate for their chronic anemia, SCD patients had 67% greater CBF than control subjects, producing a normal SvO2 and OEF. Oxygen delivery also trended higher than for controls leading to higher total CMRO2 in the SCD patients. CMRO2 increases remained significant even after correction for differences in grey and white matter volumes. We found no correlation between WBC and CMRO2when tested by population.Discussion Our study demonstrates elevated cerebral metabolism in SCD, mirroring increases in global resting energy expenditure and peripheral metabolic rate described by other groups. The etiology of the increased CMRO2 is unknown but could reflect neuroinflammation or energy demands from chronic injury/repair. Regardless, our observation at least partially explains the increase of CBF beyond predicted by anemia alone. By excluding patients with overt stroke and by correcting for differences in brain volume and composition, our results are the first CMRO2 measurements in SCD that are unconfounded by brain volume loss. Given the age differences between our study and control populations, we cannot exclude developmental differences in CMRO2 among patients and controls. However, in general, CMRO2 increases with age, which would tend to lessen rather than increase the CMRO2 differences seen in our study.Table 1ControlsSCDpAge (years)37.2 + 2.820.3 + 2.6<0.05Sex9 F, 3 M9 F, 6 MnsHemoglobin (g/dl)13.5 + 1.29.6 + 1.1<0.05WBC (103/uL)6.1 + 2.211.0 + 4.2<0.05Sa O2 (%)95.7 + 1.594.1 + 4.1nsSv O2 (%)65.6 + 6.763.6 + 8.4nsOEF30.0 + 7.132.3 + 7.4nsCBF (ml/100g/min)70.0 + 4.6116.8 + 19.1<0.05Cerebral O2 delivery (umol O2/100g/min)193.0 + 44.9239.0 + 35.7nsGrey Matter Mass (ml)499.6 + 72.0528.4 + 58.1nsWhite Matter Mass (ml)444.6 + 58.2422.9 + 59.5nsCMRO2 (umol O2/100g/min)193.1 + 44.9239.0 + 35.7<0.05(gm)CMRO2250.7 + 58.7292.7 + 39.7<0.05(wm) CMRO2175.5 + 41.1204.9 + 27.8<0.05 DisclosuresCoates:Novartis: Honoraria, Speakers Bureau; Apo Pharma: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; SHire: Consultancy, Honoraria.

Elevated Cerebral Blood Oxygen Extraction in Non-Transfused Sickle Cell Disease Patients

Introduction Chronic Transfusion Therapy (CTT) has been successful in decreasing stroke frequency in patients with sickle cell disease (SCD). Despite this, indication for CTT is largely based on empirical evidence and the mechanisms by which CTT protects the brain remain unclear. CTT improves oxygen carrying capacity and lowers hemoglobin S%, but the corresponding impact on cerebral blood flow(CBF), cerebral metabolic rate (CMRO2), and oxygen extraction fraction (OEF) is unknown. Understanding the impact of these competing influences in non-transfused (NT) and chronically transfused (CT) SCD patients will inform stroke prevention. Thus, we measured CBF, CMRO2, and OEF, in NT and CT patients with SCD using magnetic resonance imaging (MRI).Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Fourteen (6 NT, 8 CT) patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Complete blood count and hemoglobin electrophoresis were performed. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. CaO2 was calculated as the product of hemoglobin, SaO2 and the oxygen density of hemoglobin (1.36 ml/g). Phase contrast imaging of the carotid and vertebral arteries was used to measure global CBF. T2 Relaxation Under Spin Tagging (TRUST) was used to measured T2 relaxation of blood within the sagittal sinus. T2 relaxation was converted to SvO2 via previously validated calibration curves. OEF represented the difference of SaO2 andSvO2 divided bySaO2. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for brain volume calculation using BrainSuiteñ software.Results Table 1 summarizes the results. Hemoglobin and oxygen content were well matched between transfused and non transfused SCD patients. Cerebral metabolic rate was also nearly identical in the two groups. However, CT patients exhibited 25% higher CBF than NT SCD patients, allowing them to have a normal oxygen extraction fraction ~30%. In contrast, OEF in NT SCD patients was abnormally high (37.8%), suggesting a decreased extraction reserve. Total oxygenation index (TOI) by NIRS also trended lower in NT SCD patients, consistent with the greater oxygen extraction and lower cerebral venous saturations observed. Abstract 1387. TableCTL (reference)NTCTp value (NT vs CT)Hemoglobin (g/dl)13.5 ± 1.229.7 ± 1.259.7 ± 1.05nsCaO2 (umol O2/ml)9.85 ± .996.84 ± 1.176.95 ±.71nsCMRO2 (umol O2/100g/min)193.1 ± 44.9239.7 ± 35.3238.6 ± 38.3nsCBF (ml/100g/min)70.0 ± 12.8101.5 ± 16.6127.1 ± 23.5< 0.05OEF (%)30.0 ± 7.137.8. ± 3.0629.7 ± 7.53< 0.05NIRS TOI56.0 ± 4.0948.5 ± 4.2153.5 ± 8.760.076SvO2 (%)65.6 ± 6.856.2 ± 5.267.1 ± 6.7< 0.05Discussion: Chronically transfused SCD patients achieve normal brain oxygenation metrics (SvO2, OEF, and NIRS) but require very high CBF to achieve this balance (lowering flow reserve). In contrast, NT SCD patients have smaller increases in CBF but require greater oxygen extraction to meet cerebrovascular demands (lowering extraction reserve). Hemoglobin S mediate changes in oxygen dissociation, blood viscosity, red cell deformability and microvascular damage potentially mediate these differences but their interplay is complicated and requires further study. DisclosuresCoates:novartis: Consultancy, Honoraria, Speakers Bureau; shire: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria; acceleron: Consultancy, Honoraria.

Cerebral Blood Flow and Metabolic Correlates of Near Infrared Spectroscopy in Patients with Sickle Cell Disease

Introduction Tissue oxygen index (TOI), by near Infrared Spectroscopy (NIRS), is a valuable tool for noninvasive, indirect measurement of oxygen supply-demand balance. Cerebral TOI is decreased in sickle cell disease (SCD), and correlates with disease severity. Previous work suggests that cerebral TOI is inversely correlated with hemoglobin S level and chronic transfusion therapy restores TOI to normal values. Nahavandi et al. have proposed that low cerebral TOI in SCD disease can be attributed to impaired oxygen delivery and/or carrying capacity of sickle blood. Unfortunately, the specificity of cerebral TOI is still an area of active debate. In order to elucidate these mechanisms we measured global cerebral blood flow (CBF),arterial oxygen content (CaO2), oxygen delivery (DO2), arterial and venous oxygen saturation (SaO2 and SvO2) and oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in 12 healthy controls and 15 SCD patients using magnetic resonance imaging (MRI).Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Fifteen patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. MRI compatible NIRS probes were placed on the forehead and TOI was recorded throughout the entire MRI examination. SaO2 was measured via peripheral pulse oximetery. Phase Contrast (PC) of the carotid and vertebral arteries was used to measure global CBF. T2 Relaxation Under Spin Tagging (TRUST) was used to measured T2 relaxation of blood within the sagittal sinus. T2 relaxation was converted to SvO2 via calibration curves. Blood draw for hemoglobin and electrophoresis was performed. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month.Results Table 1 summarizes the relationship between cerebral TOI, age, laboratory values, and hemodynamic variables. Surprisingly, TOI was independent of indices of oxygen supply (SaO2, CBF, oxygen delivery) and oxygen demand (CMRO2); cerebral venous saturation and OEF were the only hemodynamic correlate of TOI. Total hemoglobin and percent sickle hemoglobin were equally and independently correlated with TOI with a combined r2 of 0.59 on multivariate regression (p<0.0001).Discussion This represents the first study comparing TOI to direct measurements of cerebral oxygen supply and consumption in SCD patients. We demonstrate that TOI tracks SvO2 and OEF, suggesting that it is weighted toward venous vascular beds. The relationship of TOI and HbS% has been previously described and could either shifting of the oxygen dissociation curve or mechanical disruption of microvascular integrity. TOI’s strong dependence on total hemoglobin (after correction for HbS%) is particularly startling given its independence with oxygen delivery, suggesting that total hemoglobin is acting as a surrogate marker of microvascular disease severity in SCD patients. TableParameterR2pAge (Years)0.0127nsHemoglobin (gm/dl)0.295<0.05Hemoglobin S %0.229<0.05WBC (103/uL)0.0020nsCBF ml/100g/min0.018nsSaO2 (%)0.034nsO2 delivery0.071nsSvO2 (%)0.290<0.05OEF (%)0.238<0.05CMR020.112ns DisclosuresCoates:novartis: Honoraria, Speakers Bureau; shire: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria, Speakers Bureau; acceleron: Consultancy, Honoraria.

Rapid T2- and susceptometry-based CMRO2 quantification with interleaved TRUST (iTRUST)

Susceptometry-based oximetry (SBO) and T2-relaxation-under-spin-tagging (TRUST) are two promising methods for quantifying the cerebral metabolic rate of oxygen (CMRO2), a critical parameter of brain function. We present a combined method, interleaved TRUST (iTRUST), which achieves rapid, simultaneous quantification of both susceptometry- and T2-based CMRO2 via insertion of a flow-encoded, dual-echo gradient-recalled echo (OxFlow) module within the T1 recovery portion of the TRUST sequence. In addition to allowing direct comparison between SBO- and TRUST-derived venous oxygen saturation (Yv) values, iTRUST substantially improves TRUST temporal resolution for CMRO2 quantification and obviates the need for a separate blood flow measurement following TRUST acquisition. iTRUST was compared directly to TRUST and OxFlow alone in three resting subjects at baseline, exhibiting close agreement with the separate techniques and comparable precision. These baseline data as well as simulation results support the use of two instead of the traditional four T2 preparation times for T2 fitting, allowing simultaneous quantification of susceptometry- and T2-based Yv (and CMRO2) with three- and six-second temporal resolution, respectively. In 10 young healthy subjects, iTRUST was applied during a 5% CO2 gas mixture-breathing paradigm. T2-based Yv values were lower at baseline relative to susceptometry (62.3±3.1 vs. 66.7±5.1 %HbO2, P<0.05), but increased more in response to hypercapnia. As a result, T2-based CMRO2 decreased from 140.4±9.7 to 120.0±9.5μMol/100g/min, a significant −14.6±3.6% response (P<0.0001), whereas susceptometry-based CMRO2 changed insignificantly from 123.4±18.7 to 127.9±25.7, a 3.3±9.7% response (P=0.31). These differing results are in accord with previous studies applying the parent OxFlow or TRUST sequences individually, thus supporting the reliability of iTRUST but also strongly suggesting that a systematic bias exists between the susceptometry- and T2-based Yv quantification techniques.

Quantitative assessment of global cerebral metabolic rate of oxygen (CMRO2) in neonates using MRI.

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.

Characterizing Brain Oxygen Metabolism in Patients with Multiple Sclerosis with T2-Relaxation-Under-Spin-Tagging MRI

In this study, venous oxygen saturation and oxygen metabolic changes in multiple sclerosis (MS) patients were assessed using a recently developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), which measures the superior sagittal venous sinus blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO(2)), an index of global oxygen consumption. Thirty patients with relapsing-remitting MS and 30 age-matched healthy controls were studied using TRUST at 3 T MR. The mean expanded disability status scale (EDSS) of the patients was 2.3 (range, 0 to 5.5). We found significantly increased Yv (P<0.0001) and decreased CMRO(2) (P=0.003) in MS patients (mean±s.d.: 65.9%±5.1% and 138.8±35.4 μmol per 100 g per minute) as compared with healthy control subjects (60.2%±4.0% and 180.2±24.8 μmol per 100 g per minute, respectively), implying decrease of oxygen consumption in MS. There was a significant positive correlation between Yv and EDSS and between Yv and lesion load in MS patients (n=30); on the contrary, there was a significant negative correlation between CMRO(2) and EDSS and between CMRO(2) and lesion load (n=12). There was no correlation between Yv and brain atrophy measures. This study showed preliminary evidence of the potential utility of TRUST in global oxygen metabolism. Our results of significant underutilization of oxygen in MS raise important questions regarding mitochondrial respiratory dysfunction and neurodegeneration of the disease.

QUantitative Imaging of eXtraction of oxygen and TIssue consumption (QUIXOTIC) using venular‐targeted velocity‐selective spin labeling

While oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO(2)) are fundamental parameters of brain health and function, a robust MRI-based mapping of OEF and CMRO(2) amenable to functional MRI (fMRI) has not been established. To address this issue, a novel method called QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption, or QUIXOTIC, is introduced. The key innovation in QUIXOTIC is the use of velocity-selective spin labeling to isolate MR signal exclusively from postcapillary venular blood on a voxel-by-voxel basis. Measuring the T(2) of this venular-targeted blood allows calibration to venular oxygen saturation (Y(v)) via theoretical and experimental T(2) versus blood oxygen saturation relationships. Y(v) is converted to OEF, and baseline CMRO(2) is subsequently estimated from OEF and additional cerebral blood flow and hematocrit measurements. Theory behind the QUIXOTIC technique is presented, and implications of cutoff velocity (V(CUTOFF)) and outflow time parameters are discussed. Cortical gray matter values obtained with QUIXOTIC in 10 healthy volunteers are Y(v) = 0.73 ± 0.02, OEF = 0.26 ± 0.02, and CMRO(2) = 125 ± 15 μmol/100 g min. Results are compared to global measures obtained with the T(2) relaxation under spin tagging (TRUST) technique. The preliminary data presented suggest that QUIXOTIC will be useful for mapping Y(v), OEF, and CMRO(2), in both clinical and functional MRI settings.

Calibration and validation of TRUST MRI for the estimation of cerebral blood oxygenation

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.

Noninvasive quantification of whole‐brain cerebral metabolic rate of oxygen (CMRO2) by MRI

Cerebral metabolic rate of oxygen (CMRO(2)) is an important marker for brain function and brain health. Existing techniques for quantification of CMRO(2) with positron emission tomography (PET) or MRI involve special equipment and/or exogenous agents, and may not be suitable for routine clinical studies. In the present study, a noninvasive method is developed to estimate whole-brain CMRO(2) in humans. This method applies phase-contrast MRI for quantitative blood flow measurement and T(2)-relaxation-under-spin-tagging (TRUST) MRI for venous oxygenation estimation, and uses the Fick principle of arteriovenous difference for the calculation of CMRO(2). Whole-brain averaged CMRO(2) values in young, healthy subjects were 132.1 +/- 20.0 micromol/100 g/min, in good agreement with literature reports using PET. Various acquisition strategies for phase-contrast and TRUST MRI were compared, and it was found that nongated phase-contrast and sagittal sinus (SS) TRUST MRI were able to provide the most efficient and accurate estimation of CMRO(2). In addition, blood flow and venous oxygenation were found to be positively correlated across subjects. Owing to the noninvasive nature of this method, it may be a convenient and useful approach for assessment of brain metabolism in brain disorders as well as under various physiologic conditions.

Baseline blood oxygenation modulates response amplitude: Physiologic basis for intersubject variations in functional MRI signals

Although BOLD functional MRI (fMRI) provides a useful tool for probing neuronal activities, large intersubject variations in signal amplitude are commonly observed. Understanding the physiologic basis for these variations will have a significant impact on many fMRI studies. First, the physiologic modulator can be used as a regressor to reduce variations across subjects, thereby improving statistical power for detecting group differences. Second, if a pathologic condition or a drug treatment is shown to change fMRI responses, monitoring this modulatory parameter is useful in correctly interpreting the fMRI changes to neuronal deficits/recruitments. Here we present evidence that the task-evoked fMRI signals are modulated by baseline blood oxygenation. To measure global blood oxygenation, we used a recently developed technique, T(2) relaxation under spin-tagging (TRUST) MRI, which yielded baseline oxygenation of 63.7% +/- 7.2% in the sagittal sinus with an estimation error of 1.3%. It was found that individuals with higher baseline oxygenation tend to have a smaller fMRI signal, and vice versa. For every 10% difference in baseline oxygenation across subjects, BOLD and cerebral blood flow (CBF) signals differ by -0.4% and -30.0%, respectively, when using visual stimulation. TRUST MRI is a useful measurement for fMRI studies to control for the modulatory effects of baseline oxygenation that are unique to each subject.

Quantitative evaluation of oxygenation in venous vessels using T2‐Relaxation‐Under‐Spin‐Tagging MRI

Noninvasive measurement of cerebral venous oxygenation can serve as a tool for better understanding fMRI signals and for clinical evaluation of brain oxygen homeostasis. In this study a novel technique, T2-Relaxation-Under-Spin-Tagging (TRUST) MRI, is developed to estimate oxygenation in venous vessels. This method uses the spin labeling principle to automatically isolate pure blood signals from which T2 relaxation times are determined using flow-insensitive T2-preparation pulses. The blood T2 is then converted to blood oxygenation using a calibration plot. In vivo experiments gave a baseline venous oxygenation of 64.8 +/- 6.3% in sagittal sinus in healthy volunteers (n = 24). Reproducibility studies demonstrated that the standard deviation across trials was 2.0 +/- 1.1%. The effects of repetition time and inversion time selections were investigated. The TRUST technique was further tested using various physiologic challenges. Hypercapnia induced an increase in venous oxygenation by 13.8 +/- 1.1%. On the other hand, caffeine ingestion resulted in a decrease in oxygenation by 7.0 +/- 1.8%. Contrast agent infusion (Gd-DTPA, 0.1 mmol/kg) reduced venous blood T2 by 11.2 ms. The results of this study show that TRUST MRI is a useful technique for quantitative assessment of blood oxygenation in the brain.