Functional MRI with magnetization transfer effects: Determination of BOLD and arterial blood volume changes

The primarily intravascular magnetization transfer (MT)‐independent changes in functional MRI (fMRI) can be separated from MT‐dependent changes. This intravascular component is dominated by an arterial blood volume change (ΔCBV_a) term whenever venous contributions are minimized. Stimulation‐induced ΔCBV_a can therefore be measured by a fit of signal changes to MT ratio. MT‐varied fMRI data were acquired in 13 isoflurane‐anesthetized rats during forepaw stimulation at 9.4T to simultaneously measure blood‐oxygenation‐level–dependent (BOLD) and ΔCBV_a response in somatosensory cortical regions. Transverse relaxation rate change (ΔR₂) without MT was –0.43 ± 0.15 s^?1, and MT ratio decreased during stimulation. ΔCBV_a was 0.46 ± 0.15 ml/100 g, which agrees with our previously‐presented MT‐varied arterial‐spin‐labeled data (0.42 ± 0.18 ml/100 g) in the same animals and also correlates with ΔR₂ without MT. Simulations show that ΔCBV_a quantification errors due to potential venous contributions are small for our conditions. Magn Reson Med 60:1518–1523, 2008. © 2008 Wiley‐Liss, Inc.     

Continuous assessment of perfusion by tagging including volume and water extraction (CAPTIVE): A steady-state contrast agent technique for measuring blood flow,relative blood volume fraction,and the water extraction fraction

A new technique, CAPTIVE, that is a synthesis of arterial spin labeling (ASL) blood flow and steady-state susceptibility con trast relative blood volume imaging is described. Using a single injection of a novel, long half-life intravascular magnetopharma-ceutical with a high tissue:blood susceptibility difference (Δ χ) to ΔR1 ratio, changes in tissue transverse relaxivity (ΔR2 or ΔR2*) that arise from changes in blood volume were measured, while preserving the ability to measure blood flow using traditional T₁ -based ASL techniques. This modification permits the contin uous measurement of both blood flow and blood volume. Also, because the contrast agent can be used to remove the signal from intravascular spins, it is possible to measure the first-pass water extraction fraction. Contrast-to-noise is easily traded off with repetition rate, allowing the use of non-EPI scanners and more flexible imaging paradigms. The basic theory of these measurements, several experimental scenarios, and validating results are presented. Specifically, the PaCO₂-reactivity of mi-crovascular and total relative cerebral blood volume (rCBV), ce rebral blood flow (CBF), and the water extraction-flow product (EF) in rats with the new contrast agent MPEG-PL-DyDTPA is measured, and the values are concordant with those of previous literature. As an example of one possible application, continuous flow and volume measurements during transient focal ischemia are presented. It is believed that CAPTIVE imaging will yield a more complete picture of the hemodynamic state of an organ, and has further application for understanding the origins of the BOLD effect.     

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.     

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.     

Effects of acute normovolemic hemodilution on T2* - weighted images of rat brain

Acute normovolemic hernodilution (HD) was induced in anesthetized rats to assess the effect of changes in hematocrit (Hct) on signal intensity in T₂*-weighted magnetic resonance (MR) images. Other relevant physiological parameters were maintained invariant. Two degrees of HD were induced: mild (Hct reduced from 42.6 ± 2.2% to 33.4 ± 2.1%) and moderate (Hct reduced from 44.6 ± 2.7% to 26.2 ± 1.7%). A two-dimensional gradient-echo sequence was used to monitor signal changes with high temporal resolution before, during, and after HD protocols. The time course of signal intensity change was closely related to that of changes in Hct. Corresponding changes in R₂* (ΔR₂*) with respect to the pre-HD state were calculated for the brain parenchyma. Average ΔR₂* values of ?0.24 ± 0.06 s^?1 and ?0.40 ± 0.07 s^?1 were obtained for the mild and moderate HD groups, respectively, during the final 2 min of MR imaging (proximal to correlative measurements of Hct). MR measured ΔR₂* values were in close agreement with the expected changes in R₂* predicted from theory when the measured changes in Hct were used as independent variables. These data are in good agreement with the current understanding of the effects of changes in the intravascular concentration of deoxyhemoglobin on induced magnetic susceptibility and hold promise for quantitative measurement of brain oxygenation in vivo.     

Bayesian estimation of changes in transverse relaxation rates

Although the biasing of R*₂ estimates by assuming magnitude MR data to be normally distributed has been described, the effect on changes in R*₂ (ΔR*₂), such as induced by a paramagnetic contrast agent, has not been reported. In this study, two versions of a novel Bayesian maximum a posteriori approach for estimating ΔR*₂ are described and evaluated: one that assumes normally distributed data and the other, Rice‐distributed data. The approach enables the robust, voxelwise determination of the uncertainty in ΔR*₂ estimates and provides a useful statistical framework for quantifying the probability that a pixel has been significantly enhanced. This technique was evaluated in vivo, using ultrasmall superparamagnetic iron oxide particles in orthotopic murine prostate tumors. It is shown that assuming magnitude data to be normally distributed causes ΔR*₂ to be underestimated when signal‐to‐noise ratio is modest. However, the biasing effect is less than is found in R*₂ estimates, implying that the simplifying assumption of normally distributed noise is more justifiable when evaluating ΔR*₂ compared with when evaluating precontrast R*₂ values. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Modeling of Look‐Locker estimates of the magnetic resonance imaging estimate of longitudinal relaxation rate in tissue after contrast administration

This paper models the behavior of the longitudinal relaxation rate of the protons of tissue water R₁ (R₁ = 1/T₁), measured in a Look‐Locker experiment at 7 Tesla after administration of a paramagnetic contrast agent (CA). It solves the Bloch‐McConnell equations for the longitudinal magnetization of the protons of water in a three‐site two‐exchange (3S2X) model with boundary conditions appropriate to repeated sampling of magnetization. The extent to which equilibrium intercompartmental water exchange kinetics affect monoexponential estimates of R₁ after administration of a CA in dynamic contrast enhanced experiment is described. The relation between R₁ and tissue CA concentration was calculated for CA restricted to the intravascular, or to the intravascular and extracellular compartments, by varying model parameters to mimic experimental data acquired in a rat model of cerebral tumor. The model described a nearly linear relationship between R₁ and tissue concentration of CA, but demonstrated that the apparent longitudinal relaxivity of CA depends upon tissue type. The practical consequence of this finding is that the extended Patlak plot linearizes the ΔR₁ data in tissue with leaky microvessels, accurately determines the influx rate of the CA across these microvessels, but underestimates the volume of intravascular blood water. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.     

Effects of Myocardial Water Exchange on T1 Enhancement during Bolus Administration of MR Contrast Agents

Interpretation of first-pass myocardial perfusion studies employing bolus administration of T₁ magnetic resonance (MR) contrast agents requires an understanding of the relationship between contrast concentration and image pixel intensity. The potential effects of myocardial water exchange rates among the intravascular, interstitial, and cellular compartments on this relationship are controversial. We directly studied these issues in isolated, nonbeating canine interventricular septa. Myocardial T₁ was measured three times/s during bolus transit of intravascular (albumin-Gd-DTPA and poly-lysine-Gd-DTPA) and extracellular (gadoteridol) contrast agents. For polylsine-Gd-DTPA, the peak changes in myocardial 1/T₁ (ΔR1) scaled nonlinearly with perfusate contrast concentration whereas a linear relationship would be expected for fast water exchange among the vascular, interstitial, and cellular compartments. For all agents, the peak ΔR1 were much smaller than the values expected on the basis of fast myocardial water exchange. The data demonstrate that in isolated myocardial tissue, myocardial T₁ enhancement during bolus administration of contrast can be strongly affected by myocardial water exchange for both intravascular and extracellular MR contrast agents.     

Dynamic and simultaneous MR measurement of R1 and R2* changes during respiratory challenges for the assessment of blood and tissue oxygenation

This work presents a novel method for the rapid and simultaneous measurement of R₁ and R₂* relaxation rates. It is based on a dynamic short repetition time steady‐state spoiled multigradient‐echo sequence and baseline R₁ and B₁ measurements. The accuracy of the approach was evaluated in simulations and a phantom experiment. The sensitivity and specificity of the method were demonstrated in one volunteer and in four patients with intracranial tumors during carbogen inhalation. We utilized (ΔR₂*, ΔR₁) scatter plots to analyze the multiparametric response amplitude of each voxel within an area of interest. In normal tissue R₂* decreased and R₁ increased moderately in response to the elevated blood and tissue oxygenation. A strong negative ΔR₂* and ΔR₁ response was observed in veins and some tumor areas. Moderate positive ΔR₂* and ΔR₁ response amplitudes were found in fluid‐rich tissue as in cerebrospinal fluid, peritumoral edema, and necrotic areas. The multiparametric approach was shown to increase the specificity and sensitivity of oxygen‐enhanced MRI compared to measuring ΔR₂* or ΔR₁ alone. It is thus expected to provide an optimal tool for the identification of tissue areas with low oxygenation, e.g., in tumors with compromised oxygen supply. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

Enhancement of gas‐filled microbubble R2* by iron oxide nanoparticles for MRI

Gas‐filled microbubbles have the potential to become a unique intravascular MR contrast agent due to their magnetic susceptibility effect, biocompatibility, and localized manipulation via ultrasound cavitation. However, microbubble susceptibility effect is relatively weak when compared with other intravascular MR susceptibility contrast agents. In this study, enhancement of microbubble susceptibility effect by entrapping monocrystalline iron oxide nanoparticles (MIONs) into polymeric microbubbles was investigated at 7 T in vitro. Apparent T₂ enhancement (ΔR₂*) induced by microbubbles was measured to be 79.2 ± 17.5 sec^?1 and 301.2 ± 16.8 sec^?1 for MION‐free and MION‐entrapped polymeric microbubbles at 5% volume fraction, respectively. ΔR₂* and apparent transverse relaxivities (r₂*) for MION‐entrapped polymeric microbubbles and MION‐entrapped solid microspheres (without gas core) were also compared, showing the synergistic effect of the gas core with MIONs. This is the first experimental demonstration of microbubble susceptibility enhancement for MRI application. This study indicates that gas‐filled polymeric microbubble susceptibility effect can be substantially increased by incorporating iron oxide nanoparticles into microbubble shells. With such an approach, microbubbles can potentially be visualized with higher sensitivity and lower concentrations by MRI. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.     

Dynamic hysteresis between gradient echo and spin echo attenuations in dynamic susceptibility contrast imaging

Perfusion measurements using dynamic susceptibility contrast imaging provide additional information about the mean vessel size of microvasculature when supplemented with a dual gradient echo (GE) – spin echo (SE) contrast. Dynamic increase in the corresponding transverse relaxation rate constant changes, ΔR_2GE and ΔR_2SE, forms a loop on the (Δ, ΔR_2GE) plane, rather than a reversible line. The shape of the loop and the direction of its passage differentiate between healthy brain and pathological tissue, such as tumour and ischemic tissue. By considering a tree model of microvasculature, the direction of the loop is found to be influenced mainly by the relative arterial and venous blood volume, as well as the tracer bolus dispersion. A parameter Λ is proposed to characterize the direction and shape of the loop, which might be considered as a novel imaging marker for describing the pathology of cerebrovascular network. Magn Reson Med 69:981–991, 2013. © 2012 Wiley Periodicals, Inc.     

Temporal changes in the T1 and T2 relaxation rates (ΔR1 and ΔR2) in the rat brain are consistent with the tissue‐clearance rates of elemental manganese

Temporal changes in the T₁ and T₂ relaxation rates (ΔR₁ and ΔR₂) in rat olfactory bulb (OB) and cortex were compared with the absolute manganese (Mn) concentrations from the corresponding excised tissue samples. In vivo T₁ and T₂ relaxation times were measured before, and at 1, 7, 28, and 35 d after intravenous infusion of 176 mg/kg MnCl₂. The values of ΔR₁, ΔR₂, and absolute Mn concentration peaked at day 1 and then declined to near control levels after 28 to 35 d. The Mn bioelimination rate from the rat brain was significantly faster than that reported using radioisotope techniques. The R₁ and R₂ relaxation rates were linearly proportional to the underlying tissue Mn concentration and reflect the total absolute amount of Mn present in the tissue. The in vivo Mn r₁ and r₂ tissue relaxivities were comparable to the in vitro values for aqueous Mn²⁺. These results demonstrate that loss of manganese‐enhanced MRI (MEMRI) contrast after systemic Mn²⁺ administration is due to elimination of Mn²⁺ from the brain. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Quantitative measurements of regional cerebral blood volume using MRI in rats: Effects of arterial carbon dioxide tension and mannitol

A three-dimensional (3D) T₁-weighted sequence was used to acquire high spatial resolution whole brain images in rats before and after the injection of an intravascular contrast agent. These T₁-weighted images were used to estimate regional cerebral blood volume (rCBV) as a percentage of blood volume in each voxel. Ventilation was manipulated to investigate the effects of altered arterial carbon dioxide tension (PaCO₂) on rCBV. In addition, different doses of a hypertonic mannitol solution were used to investigate the sensitivity of the proposed method in a serial monitoring paradigm. An rCBV of 2.40% ± 0.34% was obtained before any physiological manipulation, in good agreement with literature values using alternative techniques. Using this method, it was found that there exists a linear relationship between PaCO₂ and rCBV (R² = 0.77) and that rCBV increased in a dose and time dependent fashion in mannitol-treated rats. High signal-to-noise was available due to the substantial increase in blood signal from the intravascular contrast agent.     

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.     

In vivo measurement of ADC change due to intravascular susceptibility variation.

The apparent diffusion coefficient (ADC) of extravascular tissue water in rat brains was measured in response to step-wise injections of the superparamagnetic intravascular contrast agent AMI-227. These data were normalized and compared with measured changes in R2* and blood magnetic susceptibility. Linear regression showed that ADC changes 33%/ppm shift of intravascular susceptibility and 0.43% s(-1) change in R2*. These changes correspond to a predicted ADC change of approximately 6% for a change between fully oxygenated and fully deoxygenated blood. The source of these ADC changes was confirmed to be background gradients within the sample by the use of diffusion weighting with bipolar gradients of odd symmetry designed to cancel such background gradient effects on ADC. The results suggest that diffusion-weighted imaging is sensitive to blood-oxygenation and may provide a means of measuring changes in blood oxygen. They also provide estimates of the potential contribution of susceptibility changes to changes in ADC that occur, for example, in stroke and seizure.     

Sensitivity of USPIO-enhanced R2 imaging to dynamic blood volume changes in the rat kidney

Purpose:

To determine whether MRI in combination with an intravascular contrast agent is sensitive to pharmacologically induced vasodilation and vasoconstriction in the rat kidney.

Materials and Methods:

R₂ imaging was performed in 25 Sprague Dawley rats at 3 Tesla in the presence of ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO) agent with a long plasma half‐life. R₂ changes were measured following manipulation of blood volume by intravenous administration of adenosine, a short‐acting vasodilator, or N^G‐nitro‐L‐arginine methyl ester (L‐NAME), a long‐acting nitric oxide synthase inhibitor with known vasoconstrictive effects. As a control, R₂ responses to adenosine and L‐NAME were also examined in the absence of ferumoxytol.

Results:

In the presence of ferumoxytol, adenosine induced a significant increase in R₂, while L‐NAME produced a reduction, although the latter was not statistically significant. Control experiments revealed small R₂ changes in the absence of ferumoxytol. An incidental finding was that the cross‐sectional area of the kidney also varied dynamically with adenosine and L‐NAME.

Conclusion:

Our results suggest that ferumoxytol‐enhanced R₂ imaging is sensitive to adenosine‐induced vasodilation. The responses to L‐NAME, however, were not statistically significant. The variations in kidney size and the R₂ changes in the absence of ferumoxytol may reflect alterations in the volume of the renal tubules. J. Magn. Reson. Imaging 2011;33:1091–1099. © 2011 Wiley‐Liss, Inc.     

The MRI‐measured arterial input function resulting from a bolus injection of Gd‐DTPA in a rat model of stroke slightly underestimates that of Gd‐[14C]DTPA and marginally overestimates the blood‐to‐brain influx rate constant determined by Patlak plots

The hypothesis that the arterial input function (AIF) of gadolinium‐diethylenetriaminepentaacetic acid injected by intravenous bolus and measured by the change in the T₁‐relaxation rate (ΔR₁; R₁ = 1/T₁) of superior sagittal sinus blood (AIF‐I) approximates the AIF of ¹⁴C‐labeled gadolinium‐diethylenetriaminepentaacetic acid measured in arterial blood (reference AIF) was tested in a rat stroke model (n = 13). Contrary to the hypothesis, the initial part of the ΔR₁‐time curve was underestimated, and the area under the normalized curve for AIF‐I was about 15% lower than that for the reference AIF. Hypothetical AIFs for gadolinium‐diethylenetriaminepentaacetic acid were derived from the reference AIF values and averaged to obtain a cohort‐averaged AIF. Influx rate constants (K_i) and proton distribution volumes at zero time (V_p + V_o) were estimated with Patlak plots of AIF‐I, hypothetical AIFs, and cohort‐averaged AIFs and tissue ΔR₁ data. For the regions of interest, the K_is estimated with AIF‐I were slightly but not significantly higher than those obtained with hypothetical AIFs and cohort‐averaged AIF. In contrast, V_p + V_o was significantly higher when calculated with AIF‐I. Similar estimates of K_i and V_p + V_o were obtained with hypothetical AIFs and cohort‐averaged AIF. In summary, AIF‐I underestimated the reference AIF; this shortcoming had little effect on the K_i calculated by Patlak plot but produced a significant overestimation of V_p + V_o. Magn Reson Med 63:1502–1509, 2010. © 2010 Wiley‐Liss, Inc.     

Human whole blood T2 relaxometry at 3 Tesla

A precise understanding of human blood spin–spin relaxation is of major importance for numerous applications, particularly functional magnetic resonance imaging (fMRI), which is increasingly performed at 3 Tesla. It is well known that T₂ measured from partially deoxygenated blood depends on the Carr–Purcell Meiboom–Gill (CPMG) refocusing interval (τ₁₈₀) and on blood oxygenation (Y), yet debate remains over the quantification of this phenomenon, primarily with respect to the accuracy of its characterization by the diffusion and fast two‐site exchange models. In this study, a detailed characterization of the deoxygenation‐induced T₂ reduction in human whole blood, as well as a comprehensive assessment of the role of τ₁₈₀, were performed at 3 T. The diffusion model was found to better fit the observed T₂ behavior as compared with the exchange model. The estimated diffusion‐model parameters suggest the T₂ decay enhancement at 3 T is due to a linear increase in the magnitude of deoxygenation‐induced field inhomogeneities with field strength. These findings also confirm the potential of τ₁₈₀ manipulation in measuring changes in venous blood volume. Magn Reson Med 61:249–254, 2009. © 2009 Wiley‐Liss, Inc.     

Investigating temporal fluctuations in tumor vasculature with combined carbogen and ultrasmall superparamagnetic iron oxide particle (CUSPIO) imaging

A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R₂* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ΔR₂*_carbogen followed by positive ΔR₂*_USPIO with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ΔR₂*_carbogen but no significant ΔR₂*_USPIO were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining ΔR₂*_carbogen and ΔR₂*_USPIO with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture. Magn Reson Med 66:227–234, 2011. © 2011 Wiley‐Liss, Inc.     

Experimental determination of the BOLD field strength dependence in vessels and tissue

High resolution functional MRI (fMRI) experiments were performed in human visual cortex at 0.5, 1.5, and 4 T to determine the blood oxygenation level dependent (BOLD) field strength response within regions of obvious venous vessels and cortical gray matter (“tissue”). T₂*-weighted FLASH images were collected in single- and multi-echo mode and used to determine the intrinsic BOLD parameters, namely, signal-to-noise ratio (Ψ), the apparent transverse relaxation rate (R₂*) and the change in R₂* (ΔR₂*) between the activated and baseline states. The authors find the average percentage signal change (ΔS/S, measured at TE = T₂*) to be large in vessels (13.3 ± 2.3%, 18.4 ± 4.0%, and 15.1 ± 1.2%) compared with that in tissue (1.4 ± 0.7%, 1.9 ± 0.7%, and 3.3 ± 0.2%) at 0.5, 1.5, and 4 T, respectively. The signal-to-noise ratio in optimized, fully relaxed proton density weighted gradient echo images was found to increase linearly with respect to the static magnetic field strength (B₀). The predicted upper bound on BOLD contrast-to-noise ratio (ΔS/R)_max as a function of field strength was calculated and found to behave less than linearly in voxels containing vessels larger than the voxel itself and greater than linearly in voxels containing a mixture of capillaries and veins/venules with a diameter less than that of the voxel.