Boosting 19F MRI—SNR efficient detection of paramagnetic contrast agents using ultrafast sequences

¹⁹F MRI offers high specificity but usually low sensitivity. Here, paramagnetic relaxation enhancement is assessed as a method to improve SNR efficiency in ¹⁹F MRI. Compounds with short relaxation times are used that combine fluorine and a paramagnetic ion within the same molecule. Different molecular designs provide T₁ values in the range of 1.4–15 ms and /T₁ ratios from 0.3 to 1. Gradient echo, as well as ultrafast radial MR sequences, is optimized to achieve highest SNR efficiency. Compared to nonparamagnetic compounds, ultrafast sequences can yield a gain of up to a factor 27 in sensitivity, whereas the gain with gradient echo is only factor 11. Comparison among the paramagnetic compounds shows that /T₁ close to unity is a prerequisite for highest SNR efficiency gain and that best results are obtained for compounds with T₁ in the range of 1–5 ms. Magn Reson Med 69:1056–1062, 2013. © 2012 Wiley Periodicals, Inc.     

Improved RF performance of travelling wave MR with a high permittivity dielectric lining of the bore

Application of travelling wave MR to human body imaging is restricted by the limited peak power of the available RF amplifiers. Nevertheless, travelling wave MR advantages like a large field of view excitation and distant location of transmit elements would be desirable for whole body MRI. In this work, improvement of the efficiency of travelling wave MR is demonstrated. High permittivity dielectric lining placed next to the scanner bore wall effectively reduces attenuation of the travelling wave in the longitudinal direction and at the same time directs the radial power flow toward the load. First, this is shown with an analytical model of a metallic cylindrical waveguide with the dielectric lining next to the wall and loaded with a cylindrical phantom. Simulations and experiments also reveal an increase of efficiency in the center of the bore for travelling wave MR with a dielectric lining. Phantom experiments show up to a 2‐fold gain in with the dielectric lining. This corresponds to a 4‐fold increase in power efficiency of travelling wave MR. In vivo experiments demonstrate an 8‐fold signal‐to‐noise ratio gain with the dielectric lining. Overall, it is shown that dielectric lining is a constructive method to improve efficacy of travelling wave MR. Magn Reson Med 70:885–894, 2013. © 2012 Wiley Periodicals, Inc.     

High‐resolution cerebral blood volume imaging in humans using the blood pool contrast agent ferumoxytol

Cerebral blood volume maps are usually acquired using dynamic susceptibility contrast imaging which inherently limits the spatial resolution and signal to noise ratio of the images. In this study, we used ferumoxytol (AMAG Pharmaceuticals, Inc., Cambridge, MA), an FDA‐approved compound, to obtain high‐resolution cerebral blood volume maps with a steady‐state approach in seven healthy volunteers. maps (0.8 × 0.8 × 1 mm³) were acquired before and after injection of ferumoxytol and an intraindividual normalization protocol was used to obtain quantitative values. The results show excellent contrast between white and gray matter as well as fine highly detailed vascular structures. An average blood volume of 4% was found in the brain of all volunteers, consistent with prior literature values. A linear relationship was found between ferumoxytol dose (mg/kg) and (1/s) in gray (R² = 0.98) and white matter (R² = 0.98). A quadratic relationship was found in the sagittal sinus (R² = 0.98). The cerebral blood volume maps compare well with lower resolution dynamic susceptibility contrast‐MRI and their use should improve the evaluation of small and heterogeneous lesions and facilitate intrapatient and interpatient comparisons. Magn Reson Med 70:705–710, 2013. © 2012 Wiley Periodicals, Inc.     

Adiabatic RF pulse design for Bloch‐Siegert B mapping

The Bloch–Siegert (B–S) mapping method has been shown to be fast and accurate, yet it suffers from high Specific Absorption Rate (SAR) and moderately long echo time. An adiabatic RF pulse design is introduced here for optimizing the off‐resonant B–S RF pulse to achieve more B–S measurement sensitivity for a given pulse width. The extra sensitivity can be used for higher angle‐to‐noise ratio maps or traded off for faster scans. Using numerical simulations and phantom experiments, it is shown that a numerically optimized 2‐ms adiabatic B‐S pulse is 2.5 times more efficient than a conventional 6‐ms Fermi‐shaped B–S pulse. The adiabatic B–S pulse performance is validated in a phantom, and in vivo brain mapping at 3T and 7T are shown. Magn Reson Med 70:829–835, 2013. © 2012 Wiley Periodicals, Inc.     

Localization errors in MR spectroscopic imaging due to the drift of the main magnetic field and their correction

Purpose: To analyze the effect of B₀ field drift on multivoxel MR spectroscopic imaging and to propose an approach for its correction. Theory and Methods: It is shown, both theoretically and in a phantom, that for ～30 min acquisitions a linear B₀ drift (～0.1 ppm/h) will cause localization errors that can reach several voxels (centimeters) in the slower varying phase encoding directions. An efficient and unbiased estimator is proposed for tracking the drift by interleaving short (～ ), nonlocalized acquisitions on the nonsuppressed water each pulse repetition time, as shown in 10 volunteers at 1.5 and 3 T. Results: The drift is shown to be predominantly linear in both the phantom and volunteers at both fields. The localization errors are observed and quantified in both phantom and volunteers. The unbiased estimator is shown to reliably track the instantaneous frequency in vivo despite only using a small portion of the FID. Conclusion: Contrary to single‐voxel MR spectroscopy, where it leads to line broadening, field drift can lead to localization errors in the longer chemical shift imaging experiments. Fortunately, this drift can be obtained at a negligible cost to sequence timing, and corrected for in post processing. Magn Reson Med, 70:895–904, 2013. © 2012 Wiley Periodicals, Inc.     

Biodegradable,polymer encapsulated,metal oxide particles for MRI‐based cell tracking

Metallic particles have shaped the use of magnetic resonance imaging (MRI) for molecular and cellular imaging. Although these particles have generally been developed for extracellular residence, either as blood pool contrast agents or targeted contrast agents, the coopted use of these particles for intracellular labeling has grown over the last 20 years. Coincident with this growth has been the development of metal oxide particles specifically intended for intracellular residence, and innovations in the nature of the metallic core. One promising nanoparticle construct for MRI‐based cell tracking is polymer encapsulated metal oxide nanoparticles. Rather than a polymer coated metal oxide nanocrystal of the core: shell type, polymer encapsulated metal oxide nanoparticles cluster many nanocrystals within a polymer matrix. This nanoparticle composite more efficiently packages inorganic nanocrystals, affording the ability to label cells with more inorganic material. Further, for magnetic nanocrystals, the clustering of multiple magnetic nanocrystals within a single nanoparticle enhances r₂ and ${\mathit{r}}_2^{*}$ relaxivity. Methods for fabricating polymer encapsulated metal oxide nanoparticles are facile, yielding both varied compositions and synthetic approaches. This review presents a brief history into the use of metal oxide particles for MRI‐based cell tracking and details the development and use of biodegradable, polymer encapsulated, metal oxide nanoparticles and microparticles for MRI‐based cell tracking. Magn Reson Med 73:376–389, 2015. © 2014 Wiley Periodicals, Inc.     

Noncontrast‐enhanced renal angiography using multiple inversion recovery and alternating TR balanced steady‐state free precession

Noncontrast‐enhanced renal angiography techniques based on balanced steady‐state free precession avoid external contrast agents, take advantage of high inherent blood signal from the contrast mechanism, and have short steady‐state free precession acquisition times. However, background suppression is limited; inflow times are inflexible; labeling region is difficult to define when tagging arterial flow; and scan times are long. To overcome these limitations, we propose the use of multiple inversion recovery preparatory pulses combined with alternating pulse repetition time balanced steady‐state free precession to produce renal angiograms. Multiple inversion recovery uses selective spatial saturation followed by four nonselective inversion recovery pulses to concurrently null a wide range of background species while allowing for adjustable inflow times; alternating pulse repetition time steady‐state free precession maintains vessel contrast and provides added fat suppression. The high level of suppression enables imaging in three‐dimensional as well as projective two‐dimensional formats, the latter of which has a scan time as short as one heartbeat. In vivo studies at 1.5 T demonstrate the superior vessel contrast of this technique. Magn Reson Med 70:527–536, 2013. © 2012 Wiley Periodicals, Inc.     

Compensation of slice profile mismatch in combined spin‐ and gradient‐echo echo‐planar imaging pulse sequences

Combined acquisition of gradient‐echo and spin‐echo signals in MRI time series reveals additional information for perfusion‐weighted imaging and functional MRI because of differences in the sensitivity of gradient‐echo and spin‐echo measurements to the properties of the underlying vascular architecture. The acquisition of multiple echo trains within one time frame facilitates the simultaneous estimation of the transversal relaxation parameters R₂ and R. However, the simultaneous estimation of these parameters tends to be incorrect in the presence of slice profile mismatches between signal excitation and subsequent refocusing pulses. It is shown here that improvements in pulse design reduced R₂ and R estimation errors. Further improvements were achieved by augmented parameter estimation through the introduction of an additional parameter δ to correct for discordances in slice profiles to facilitate more quantitative measurements. Moreover, the analysis of time‐resolved acquisitions revealed that the temporal stability of R₂ estimates could be increased with improved pulse design, counteracting low contrast‐to‐noise ratios in spin‐echo‐based perfusion and functional MRI. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.     

Reproducibility and biological basis of in vivo T2* magnetic resonance imaging of liver metastasis of colorectal cancer

In this study, the reproducibility of MR imaging in colorectal liver metastases was assessed and values were correlated with the expression of the hypoxia‐related markers GLUT‐1 and CA‐IX as well as the relative vascular area, and the vessel density in resected tumors. The reproducibility of was analyzed in 18 patients with in total 22 colorectal liver metastases using the Bland and Altman method for the 16th, 50th, and 84th percentile values. Immunohistochemical staining was performed on 17 resected tumors obtained from 16 patients. The median of all liver metastases was 25.0 ± 5.6 ms vs. 23.0 ± 4.1 ms (median ± st.dev.) in normal liver. The coefficient of repeatability was 11.2 ms and the limits of agreement were ?13.2 ms and 9.1 ms for median values. On average, showed fair reproducibility. No correlations between values, hypoxia‐ and vascularity‐related markers were observed. Magn Reson Med, 70:1145–1152, 2013. © 2012 Wiley Periodicals, Inc.     

Coaxial waveguide for travelling wave MRI at ultrahigh fields

At high magnetic fields the performance of a volume‐type body coil inside a human sized MR‐scanner is influenced by the waveguide action of the scanner's bore. This can result in undesirable strong radio frequency fields ) outside the coil's target volume. A radio frequency (RF) transmit system, exploiting this waveguide action of the bore, is proposed in this work. A coaxial waveguide section is introduced between the antenna and the imaging region. It is shown that the coaxial waveguide has several advantages over the initially proposed travelling wave setup based on the cylindrical waveguide. First, a novel radio frequency matching principle (based on the transmission line impedance matching) is feasible with the coaxial waveguide achieving better radio frequency transmission characteristics, such as homogeneity and power efficiency of field. In case of body torso imaging, the coaxial waveguide prevents unwanted specific absorptive rate (SAR) deposition outside the target region and thus, effectively decreases local peak SAR values by factor of 5. A 3‐fold gain in the prostate can be achieved with the coaxial waveguide in comparison with the initially proposed travelling wave setup. Magn Reson Med 70:875–884, 2013. © 2012 Wiley Periodicals, Inc.     

Concurrent MR blood volume and vessel size estimation in tumors by robust and simultaneous ΔR2 and ΔR2* quantification

This work presents a novel method for concurrent estimation of the fractional blood volume and the mean vessel size of tumors based on a multi‐gradient‐echo‐multi‐spin‐echo sequence and the injection of a super‐paramagnetic blood‐pool agent. The approach further comprises a post‐processing technique for simultaneous estimation of changes in the transverse relaxation rates R₂ and R, which is robust against global B₀ and B₁ field inhomogeneities and slice imperfections. The accuracy of the simultaneous ΔR₂ and ΔR quantification approach is evaluated in a phantom. The simultaneous blood volume and vessel size estimates, obtained with MR, compare well to the immunohistological findings in a preclinical experiment (HT1080 cells, implanted in nude mice). Clinical translation is achieved in a patient with a pleomorphic sarcoma in the left pubic bone. The latter demonstrates the robustness of the technique against changes in the contrast agent concentration in blood during washout. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

B1 inhomogeneity correction of RARE MRI with transceive surface radiofrequency probes

Purpose

The use of surface radiofrequency (RF) coils is common practice to boost sensitivity in (pre)clinical MRI. The number of transceive surface RF coils is rapidly growing due to the surge in cryogenically cooled RF technology and ultrahigh-field MRI. Consequently, there is an increasing need for effective correction of the excitation field ( ) inhomogeneity inherent in these coils. Retrospective B₁ correction permits quantitative MRI, but this usually requires a pulse sequence-specific analytical signal intensity (SI) equation. Such an equation is not available for fast spin-echo (Rapid Acquisition with Relaxation Enhancement, RARE) MRI. Here we present, test, and validate retrospective B₁ correction methods for RARE.

Methods

We implemented the commonly used sensitivity correction and developed an empirical model-based method and a hybrid combination of both. Tests and validations were performed with a cryogenically cooled RF probe and a single-loop RF coil. Accuracy of SI quantification and T₁ contrast were evaluated after correction.

Results

The three described correction methods achieved dramatic improvements in B₁ homogeneity and significantly improved SI quantification and T₁ contrast, with mean SI errors reduced from >40% to >10% following correction in all cases. Upon correction, images of phantoms and mouse heads demonstrated homogeneity comparable to that of images acquired with a volume resonator. This was quantified by SI profile, SI ratio (error < 10%), and percentage of integral uniformity (PIU > 80% in vivo and ex vivo compared to PIU > 87% with the reference RF coil).

Conclusion

This work demonstrates the efficacy of three B₁ correction methods tailored for transceive surface RF probes and RARE MRI. The corrected images are suitable for quantification and show comparable results between the three methods, opening the way for T₁ measurements and X-nuclei quantification using surface transceiver RF coils. This approach is applicable to other MR techniques for which no analytical SI exists.

     

Comparison of 1H blood oxygen level–dependent (BOLD) and 19F MRI to investigate tumor oxygenation

Fluorine‐19 [¹⁹F] MRI oximetry and ¹H blood oxygen level–dependent (BOLD) MRI were used to investigate tumor oxygenation in rat breast 13762NF carcinomas, and correlations between the techniques were examined. A range of tissue oxygen partial pressure (pO₂) values was found in the nine tumors while the anesthetized rats breathed air, with individual tumor pO₂ ranging from a mean of 1 to 36 torr and hypoxic fraction (HF10) (<10 torr) ranging from 0% to 75%, indicating a large intra‐ and intertumor heterogeneity. Breathing oxygen produced significant increase in tumor pO₂ (mean ΔpO₂ = 50 torr) and decrease in HF₁₀ (P < 0.01). ¹H BOLD MRI observed using a spin echo‐planar imaging (EPI) sequence revealed a heterogeneous response and significant increase in mean tumor signal intensity (SI) (ΔSI = 7%, P < 0.01). R measured by multigradient‐echo (MGRE) MRI decreased significantly in response to oxygen (mean ΔR = ?4 s^?1; P < 0.05). A significant correlation was found between changes in mean tumor pO₂ and mean EPI BOLD ΔSI accompanying oxygen breathing (r² > 0.7, P < 0.001). Our results suggest that BOLD MRI provides information about tumor oxygenation and may be useful to predict pO₂ changes accompanying interventions. Significantly, the magnitude of the BOLD response appears to be predictive for residual tumor HFs. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Peak oxygen uptake and regional oxygenation in response to a 10‐day confinement to normobaric hypoxia

We investigated the effect of hypoxic acclimatization per se, without any concomitant influence of strenuous physical activity on muscle and cerebral oxygenation. Eight healthy male subjects participated in a crossover‐designed study. In random order, they conducted a 10‐day normoxic (CON) and a 10‐day hypoxic (EXP) confinement. Pre and post both CON and EXP confinements, subjects conducted two incremental‐load cycling exercises to exhaustion; one under normoxic, and the other under hypoxic (F_IO₂ = 0.154) conditions. Oxygen uptake (), ventilation (), and relative changes in regional hemoglobin oxygenation (Δ([HbO₂]) in the cerebral cortex and in the serratus anterior (SA) and vastus lateralis (VL) muscles were measured. No changes were observed in the CON confinement. Peak work rate and were similar pre and post in the EXP confinement, whereas increased in the EXP post normoxic and hypoxic trials (P < 0.05). The exercise‐induced drop in VL Δ[HbO₂] was less in the post‐ than pre‐EXP trial by 4.0 ± 0.4 and 4.2 ± 0.6 μM during normoxic and hypoxic exercise, respectively. No major changes were observed in cerebral or SA oxygenation. These results demonstrate that a 10‐day hypoxic exposure without any concomitant physical activity had no effect on normoxic or hypoxic , despite the enhanced VL oxygenation.     

Effects of nitrate supplementation in trained and untrained muscle are modest with initial high plasma nitrite levels

Nitrate () supplementation resulting in higher plasma nitrite () is reported to lower resting mean arterial blood pressure (MAP) and oxygen uptake (VO₂) during submaximal exercise in non‐athletic populations, whereas effects in general are absent in endurance‐trained individuals. To test whether physiologic effects of supplementation depend on local muscular training status or cardiovascular fitness, male endurance‐trained cyclists (CYC, n=9, VO₂‐max: 64±3 mL/min/kg; mean±SD) and recreational active subjects serving as a control group (CON, n=8, 46±3 mL/min/kg), acutely consumed nitrate‐rich beetroot juice ([] ~9 mmol) (NIT) or placebo (PLA) with assessment of resting MAP and energy expenditure during moderate intensity (~50% VO₂‐max) and incremental leg cycling (LEG‐ex) and arm‐cranking exercise (ARM‐ex). NIT increased (P<.001) resting plasma by ~1200% relative to PLA. Plasma increased ~25% (P<.01) with a significant change only in CYC. LEG‐ex VO₂ (~2.60 L/min), ARM‐ex VO₂ (~1.14 L/min), and resting MAP (~87 mm Hg) remained unchanged for CYC, and similarly for CON, no changes were observed for LEG‐ex VO₂ (~2.03 L/min), ARM‐ex VO₂ (~1.06 L/min), or resting MAP (~85 mm Hg). VO₂‐max was not affected by supplementation, but incremental test peak power was higher (P<.05) in LEG‐ex for CYC in NIT relative to PLA (418±47 vs 407±46 W). In both CYC and CON, high initial baseline values and small increases in plasma after NIT may have lowered the effect of the intervention implying that muscular and cardiovascular training status is likely not the only factors that influence the physiologic effects of supplementation.     

NMR imaging of changes in vascular morphology due to tumor angiogenesis

Tumor-sprouted vessels are greater in both number and diameter in comparison to their healthy counterparts. A novel technique based on magnetic susceptibility contrast mechanisms that are sensitive to varying sizes of blood vessels is presented to measure differences between the relaxation rates (1/T₂ and 1/T) in a rat glioma model and normal cerebral cortex. ΔR2 and ΔR2*, the differences between relaxation rates precontrast and postcontrast agent injection, were measured for an intravascular equilibrium contrast agent (MION) at various echo times. Since ΔR2*/ΔR2 increases as vessel size increases, this ratio can be used as a measure of the average vessel size within an ROI or a voxel. The stability and longevity of the contrast agent within the vasculature were verified (n = 2 trials), and the ratio of ΔR2*/ΔR2 between the tumor and normal cortex was measured to be 1.9 ± 0.2 (n = 4, echo time = 20 ms, and susceptibility difference (Δχ) ≈? 10^?6). This ratio compared favorably to a predicted ratio determined using histologically determined vessel sizes and theoretical Monte Carlo modeling results (1.9 ± 0.1). Maps of the ratio of ΔR2*/ΔR2 were also made on a pixel-by-pixel basis. These techniques support the hypothesis that susceptibility contrast MRI can provide useful quantitative metrics of in vivo tumor vascular morphology.     

Direct imaging and quantification of carotid plaque calcification

Carotid plaque calcification normally appears as a signal void with clinical MR sequences. Here, we describe the use of an adiabatic inversion recovery prepared two‐dimensional ultrashort echo time sequence to image and characterize carotid plaque calcification using a clinical 3‐T scanner. T₁, T, and free water content were measured for seven carotid samples, and the results were compared with micro‐CT imaging. Conventional gradient echo and fast spin echo images were also acquired for comparison. Correlations between T₁, T, free water concentration, and mineral density were performed. There was a close correspondence between inversion recovery prepared two‐dimensional ultrashort echo time morphologic and micro‐CT appearances. Carotid plaque calcification varied significantly from sample to sample, with T₁s ranging from 94 ± 19 to 328 ± 21 msec, Ts ranging from 0.31 ± 0.12 to 2.15 ± 0.25 msec, and free water concentration ranging from 5.7 ± 2.3% to 16.8 ± 3.4%. There was a significant positive correlation between T₁ (R = 0.709; P < 0.074), T (R = 0.816; P < 0.025), and free water concentration, a negative correlation between T₁ (R = 0.773; P < 0.042), T (R = 0.948; P < 0.001) and CT measured mineral density, and a negative correlation between free water concentration (R = 0.936; P < 0.002) and mineral density. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Sex differences in fitness and cardiac function during exercise in adolescents with chronic fatigue

Females demonstrate less robust Frank‐Starling mechanism with respect to cardiac preload than males at rest. We asked whether this phenomenon would also affect cardiac performance during exercise. We hypothesized that stroke volume (SV ) response to exercise would be more limited in deconditioned females such that cardiac output would be mainly rate dependent, compared with males. We conducted a chart audit of clinical exercise tests performed by adolescents with chronic fatigue. Oxygen uptake () was measured breath‐by‐breath at rest and during cycle ergometry, while cardiac output was measured by acetylene rebreathing at rest plus 2‐3 subthreshold workloads. SV response was analyzed in two ways: after normalization for body surface area (SV index, SVI ) and as percentage change from resting values. Among 304 adolescents (78% females) with chronic fatigue, 189 (80%) of 236 females and 52 (76%) of 68 males were deconditioned (peakO₂ <90% predicted). Heart rate trajectory during exercise was steeper for unfit than fit females, 70 vs 61 beat·min⁻¹ per L·min⁻¹ , (P =.003); but not for males, 47 vs 42 beat·min⁻¹ per L·min⁻¹ (P =.23). The highest measured SVI did not differ between unfit vs fit females (42.8 vs 41.5 mL·m⁻², P =.39) while fit males showed larger SV during exercise than their unfit peers (highest SVI 55.9 vs 48.0 mL·m⁻², P =.014). Both qualitative and quantitative sex differences exist in SV responses to exercise among chronically fatigued adolescents, suggesting volume loading may be more efficacious in girls.     

Effects of short‐term training and detraining on VO2 kinetics: Faster VO2 kinetics response after one training session

This study examined the time course of short‐term training and detraining‐induced changes in oxygen uptake () kinetics. Twelve men (24 ± 3 years) were assigned to either a 50% or a 70% of training intensity (n = 6 per group). was measured breath‐by‐breath. Changes in deoxygenated‐hemoglobin concentration (Δ[HHb]) were measured by near‐infrared spectroscopy. Moderate‐intensity exercise on‐transient and Δ[HHb] were modeled with a mono‐exponential and normalized (0–100% of response) and the ratio was calculated. Similar changes in time constant of () were observed in both groups. The combined group mean for decreased ～14% (32.3 to 27.9 s, P < 0.05) after one training session with a further ～11% decrease (27.9 to 24.8 s, P < 0.05) following two training sessions. The remained unchanged throughout the remaining of training and detraining. A significant “overshoot” in the ratio was decreased (albeit not significant) after one training session, and abolished (P < 0.05) after the second one, with no overshoot observed thereafter. Speeding of kinetics was remarkably quick with no further changes being observed with continuous training or during detraining. Improve matching of local O₂ delivery to O₂ utilization is a mechanism proposed to influence this response.     

Measurement of regional blood oxygenation and cerebral hemodynamics

An echo planar linewidth mapping technique, Shufflebutt, has allowed temporal measurements of changes in linewidth caused by static inhomogeneities (ΔLWSI) and transverse relaxation rate (ΔR2) in models of hypoxia and hypercapnia. We demonstrate these changes are due to intravascular susceptibility differences(Δ_X) between the blood and tissue. Contrast agent injections at a /Δ_X equivalent to that of deoxygenatetd blood showed a twofold difference between the contrast agent and physiological anoxia values. Hypercapnia decreased both ΔLWSI and ΔR2 consistent with an increase in blood oxygenation. We attribute these findings to constant oxygen extraction during an increase in blood flow, resulting in less deoxygenated venous blood and thus reduced Δ_X. For in vivoperturbations we found that ΔR/ΔR2′ ≈ 0.33, a ratio much different from that measured in whole blood phantoms (ΔR/ΔR2′ ≈ 2). This demonstrates that signal changes in these studies are produced predominantly by dephasing of extravascular protons due to field inhomogeneities produced by intravascular deoxygenated hemoglobin (deoxyHb).