High-resolution assessment of blood flow in murine RIF-1 tumors by monitoring uptake of H(2)(17)O with proton T(1rho)-weighted imaging.

Perfusion parameters, such as blood flow, are critical properties of tumors related to angiogenesis, drug delivery, radiosensitivity, bioenergetic status, and steady state levels of metabolites, such as lactate, that have been proposed as indices of tumor response to therapy. The existing MR methods for measuring tumor blood flow (TBF) have limitations related to sensitivity, spatial resolution, or dependence on other physiological properties such as vascular permeability. To address many of these difficulties, this study introduces the use of an (17)O-enriched tracer in conjunction with high-resolution, indirect MRI to measure TBF. To demonstrate the advantages of this technique, relative TBF was measured in subcutaneous RIF-1 tumors in C3H mice by monitoring the uptake of H(2) (17)O with a resolution of 0.16 x 0.31 x 3 mm in 13 sec. At this resolution, tumor heterogeneity with respect to blood flow is clearly visible. Measurement of the tracer arterial input function, which is necessary for determination of absolute blood flow, may be facilitated with improved temporal resolution.     

On- and off-resonance T(1rho) MRI in acute cerebral ischemia of the rat.

The ability of on-resonance T(1rho) (T(1rho)) and off-resonance T(1rho) (T(1rho)(off)) measurements to indicate acute cerebral ischemia in a rat model of transient middle cerebral artery (MCA) occlusion was investigated at 4.7 T. T(1rho) was determined with B(1) fields of 0.4, 0.8, and 1.6 G, and T(1rho)(off) with five offset frequencies ((Delta)omega) ranging from 0-7.5 kHz at B(1) of 0.4 G, yielding effective B(1) (B(eff)) from 0.4 to 1.8 G. Diffusion, T(1), and T(2) were also quantified. Both T(1rho) and T(1rho)(off) acquired with (Delta)(o)< 2.5 kHz showed positive contrast during the first hours of MCA occlusion in the ischemic tissue delineated by low diffusion. Interestingly, T(1rho)(off) contrast acquired with (Delta)omega > 2.5 kHz was clearly less sensitive to ischemic alterations, and developed with a delayed time course. This discrepancy is thought to be a consequence of the frequency dependency of cross-relaxation during irradiation with spin-lock pulses.     

Acute cerebral ischemia in rats studied by Carr-Purcell spin-echo magnetic resonance imaging: assessment of blood oxygenation level-dependent and tissue effects on the transverse relaxation.

Acute cerebral ischemia has been shown to be associated with an enhanced transverse relaxation rate in rat brain parenchyma, chiefly due to the blood oxygenation level-dependent (BOLD) effect. In this study, Carr-Purcell R(2) (CP R(2)), acquired both with short and long time intervals between centers of adiabatic pi-pulses (tau(CP)), was used to assess the contributions of BOLD and tissue effects to the transverse relaxation in two brain ischemia models of rat at 4.7 T. R(1rho) and diffusion MR images were also acquired in the same animals. During the first minutes of global ischemia, the long tau(CP) R(2) in brain parenchyma increased, whereas the short tau(CP) R(2) was unchanged. Based on the simulations, and using constraints of intravascular BOLD effect on parenchymal R(2), the former observation was ascribed to be due to susceptibility changes arising in the extravascular compartment. R(1rho) declined almost immediately after the onset of focal cerebral ischemia, and further declined during the evolution of ischemic damage. Interestingly, short tau(CP) CP R(2) started to decline after some 20 min of focal ischemia and declined over a time course similar to that of R(1rho), indicating that it may be an MRI marker for irreversible tissue changes in cerebral ischemia. The present results show that CP R(2) MRI can reveal both tissue- and blood-derived contrast changes in acute cerebral ischemia.     

B0 dependence of the on-resonance longitudinal relaxation time in the rotating frame (T1rho) in protein phantoms and rat brain in vivo.

On-resonance longitudinal relaxation time in the rotating frame (T1rho) has been shown to provide unique information during the early minutes of acute stroke. In the present study, the contributions of the different relaxation mechanisms to on-resonance T1rho relaxation were assessed by determining relaxation rates (R1rho) in both protein phantoms and in rat brain at 2.35, 4.7, and 9.4 T. Similar to transverse relaxation rate (R2), R1rho increased substantially with increasing magnetic field strength (B0). The B0 dependence was more pronounced at weak spin-lock fields. In contrast to R1rho, longitudinal relaxation rate (R1) decreased as a function of increasing B0 field. The present data argue that dipole-dipole interaction forms only one pathway for T1rho relaxation and the contributions from other physicochemical factors need to be considered.     

Compensation for spin-lock artifacts using an off-resonance rotary echo in T1rhooff-weighted imaging.

The origin of image artifacts in an off-resonance spin-locking experiment is shown to be imperfections in the excitation flip angle. A pulse sequence for off-resonance spin locking is implemented that compensates for imperfections in the excitation flip angle through an off-resonance rotary echo. The off-resonance rotary echo alternates the frequency offset and phase of the RF transmitter during two spin-locking pulses of equal duration. The underlying theory is detailed, and MR images demonstrate the effectiveness of the technique in agarose gel phantoms and in in vivo human brain at 3T.     

Quantification of rodent cerebral blood flow (CBF) in normal and high flow states using pulsed arterial spin labeling magnetic resonance imaging

PURPOSE: To implement a pulsed arterial spin labeling (ASL) technique in rats that accounts for cerebral blood flow (CBF) quantification errors due to arterial transit times (dt)-the time that tagged blood takes to reach the imaging slice-and outflow of the tag. MATERIALS AND METHODS: Wistar rats were subjected to air or 5% CO(2), and flow-sensitive alternating inversion-recovery (FAIR) perfusion images were acquired. For CBF calculation, we applied the double-subtraction strategy (Buxton et al., Magn Reson Med 1998;40:383-396), in which data collected at two inversion times (TIs) are combined. RESULTS: The ASL signal fell off more rapidly than expected from TI = one second onward, due to outflow effects. Inversion times for CBF calculation were therefore chosen to be larger than the longest transit times, but short enough to avoid systematic errors caused by outflow of tagged blood. Using our method, we observed a marked regional variability in CBF and dt, and a region dependent response to hypercapnia. CONCLUSION: Even when flow is accelerated, CBF can be accurately determined using pulsed ASL, as long as dt and outflow of the tag are accounted for.     

Advantages of frequency-domain modeling in dynamic-susceptibility contrast magnetic resonance cerebral blood flow quantification.

In dynamic-susceptibility contrast magnetic resonance perfusion imaging, the cerebral blood flow (CBF) is estimated from the tissue residue function obtained through deconvolution of the contrast concentration functions. However, the reliability of CBF estimates obtained by deconvolution is sensitive to various distortions including high-frequency noise amplification. The frequency-domain Fourier transform-based and the time-domain singular-value decomposition-based (SVD) algorithms both have biases introduced into their CBF estimates when noise stability criteria are applied or when contrast recirculation is present. The recovery of the desired signal components from amid these distortions by modeling the residue function in the frequency domain is demonstrated. The basic advantages and applicability of the frequency-domain modeling concept are explored through a simple frequency-domain Lorentzian model (FDLM); with results compared to standard SVD-based approaches. The performance of the FDLM method is model dependent, well representing residue functions in the exponential family while less accurately representing other functions.     

Reproducibility of total cerebral blood flow measurements using phase contrast magnetic resonance imaging

PURPOSE: To evaluate reproducibility of total cerebral blood flow (CBF) measurements with phase contrast magnetic resonance imaging (pcMRI). MATERIALS AND METHODS: We repeated total CBF measurements in 15 healthy volunteers with and without cardiac triggering, and with and without repositioning. In eight volunteers measurements were performed at two different occasions. In addition, measurement of flow in a phantom was performed to validate MR measurements. RESULTS: A difference of 40.4 ml/minute was found between CBF measurements performed with and without triggering (P < 0.05). For repeated triggered measurements, the coefficient of variation (CV) was 7.1%, and for nontriggered measurements 10.3%. For repeated measurements with repositioning, the CV was 7.1% with and 11.2% without triggering. Repeated measurements at different occasions showed a CV of 8.8%. Comparing measured with real flow in the phantom, the triggered differed 4.9% and the nontriggered 8.3%. CONCLUSION: The findings of this study demonstrate that pcMRI is a reliable method to measure total CBF in terms of both accuracy and reproducibility.     

A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats.

The vasoconstrictive peptide endothelin-1 (ET-1) has been used previously to transiently occlude the middle cerebral artery (MCA) in rats. However, the duration of the resulting reduction in cerebral blood flow (CBF) and the reperfusion characteristics are poorly understood. In this study perfusion and T(2)-weighted MRI were used together with histology to characterize the cerebral perfusion dynamics and lesion development following ET-1 injection. Twenty-two rats received an intracerebral injection of ET-1 adjacent to the MCA. CBF was reduced to 30-50% of control levels, and a significant reduction persisted for 16 h in the cortex and 7 h in the striatum. The lesion size measured by T(2)-weighted imaging at 48 h correlated with the final infarct size measured by histology at 7 d. The sustained reduction in CBF and the gradual development of the ischemic lesion resemble human stroke evolution, suggesting that this model may be useful for evaluating therapeutic agents, particularly when treatment is delayed.     

Quantitative T1rho NMR spectroscopy of rat cerebral metabolites in vivo: effects of global ischemia.

The NMR relaxation times (T(1rho), T(2), and T(1)) of water, N-acetylaspartate (NAA), creatine (Cr), choline-containing compounds (Cho), and lactate (Lac) were quantified in rat brain at 4.7 T. In control animals, the cerebral T(1rho) figures, as determined with a spin-lock field of 1.0 G, were 575 +/- 30 ms, 380 +/- 19 ms, 705 +/- 53 ms, and 90 +/- 1 ms for NAA, Cr, Cho, and water, respectively. The T(1rho) figures were 62-103% longer than their respective T(2) values determined by a multiecho method. In global (ischemic) ischemia, T(1rho) of NAA declined by 34%, that of Cr and Cho did not change, and that of water increased by 10%. The T(1rho) of lactate in ischemic brain was 367 +/- 44 ms. Similar patterns of changes were observed in the multiecho T(2) of these cerebral metabolites. The T(1) of water and NAA changed in a fashion similar to that of T(1rho) and T(2). These results show differential responses in metabolite and water T(1rho) relaxation times following ischemia, and indicate that metabolite T(1rho) and T(2) relaxation times behave similarly in the ischemic brain. The contributions of dipolar and nondipolar effects on T(1rho) relaxation in vivo are discussed in this work.     

Rotating-frame intermolecular double-quantum spin-lattice relaxation T1rho, DQC-weighted magnetic resonance imaging.

In this study, spin-locking techniques were added as a part of intermolecular multiple-quantum experiments, thereby introducing the concept of rotating-frame intermolecular double-quantum spin-lattice relaxation, T(1rho, DQC). A novel magnetic resonance imaging methodology based on intermolecular multiple-quantum coherences is demonstrated on a 7.05-T microimaging scanner. The results clearly reveal that the intermolecular double-quantum coherence T(1rho, DQC)-weighted imaging technique provides an alternative contrast mechanism to conventional imaging.     

Assessment of cerebral blood flow reserve using functional magnetic resonance imaging

Imaging of activated brain areas based on changes of blood deoxyhemoglobin levels is now possible with MRI. Acetazolamide (ACZ) increases cerebral blood flow (CBF) without changing cerebral oxygen consumption; this results in signal changes observed in gradient echo MR images from the areas with an increase in CBF. We assessed signal changes after ACZ application in seven healthy subjects with a conventional 1.5-T MRI scanner. The susceptibility-sensitized three-dimensional fast low-angle shot (FLASH) sequence was used to visualize signal changes induced by ACZ. We analyzed anatomic localization of different ranges of detected signal changes. ACZ caused significant signal changes in the gray matter and at the edge of the cerebral cortex, the latter corresponding to draining surface veins. No significant differences were seen among different brain areas within the same slice. Using the maximum intensity projection technique, we were able to partially separate signal changes originating in draining veins from signal originating in the gray matter microvasculature. Signal changes from the microvessels reflect cerebrovascular reserve. Blood-oxygen-level-dependent (BOLD) based MRI can evaluate CBF reserve with high spatial and temporal resolution. To assess cerebrovascular reserve, it is necessary to separate signal changes originating in large vessels from signal from brain microvasculature.     

Effects of intracellular pH, blood, and tissue oxygen tension on T1rho relaxation in rat brain.

The effects of intracellular pH (pH(i)), paramagnetic macroscopic, and microscopic susceptibility on T(1) in the rotating frame (T(1rho)) were studied in rat brain. Intracellular acidosis was induced by hypercapnia and pH(i), T(1rho), T(2), diffusion, and cerebral blood volume (CBV) were quantified. Taking into account the CBV contribution, a prolongation of parenchymal T(1rho) by 4.5% was ascribed to a change in tissue water relaxation caused by a one unit drop in pH(i). Blood T(1rho) was found to prolong linearly with blood oxygenation saturation (Y). The macroscopic susceptibility contribution to parenchymal T(1rho) was assessed both through BOLD and an iron oxide contrast agent, AMI-227. The T(1rho) data from these experiments could be described by intravascular effects with insignificant effects of susceptibility gradients on tissue water. Tissue oxygen tension (PtO(2)) was manipulated and monitored with microelectrodes to assess its plausible contribution to microscopic susceptibility and relaxation. Parenchymal T(1rho) was virtually unaffected by variations in the PtO(2), but T(1) was shortened in hyperoxia and T(2) showed a negative BOLD effect in hypoxia. It is demonstrated that pH(i) directly modulates tissue T(1rho), possibly through its effect on proton exchange; however, neither BOLD nor PtO(2) directly influence tissue T(1rho). The observations are discussed in the light of physicochemical mechanisms contributing to the ischemic T(1rho) changes.     

Perfusion imaging by a flow-sensitive alternating inversion recovery (Fair) technique: Application to functional brain imaging

Perfusion is a crucial physiological parameter for tissue function. To obtain perfusion-weighted images and consequently to measure cerebral blood flow (CBF), a newly developed flow-sensitive alternating inversion recovery (FAIR) technique was used. Dependency of FAIR signal on inversion times (TI) was examined; signal is predominantly located in large vessels at short TI, whereas it is diffused into gray matter areas at longer TI. CBF of gray matter areas in the human brain is 71 ± 15 SD ml/100 g/min (n = 6). In fMRI studies, micro- and macrovessel inflow contributions can be obtained by adjusting TIs. Signal changes in large vessel areas including the scalp were seen during finger opposition at a TI of 0.4 s; however, these were not observed at a longer TI of 1.4 s. To compare with commonly used BOLD and slice selective inversion recovery techniques, FAIR and BOLD images were acquired at the same time during unilateral finger opposition. Generally, activation sites determined by three techniques are consistent. However, activation of some areas can be detected only by FAIR, not by BOLD, suggesting that the oxygen consumption increase couples with the CBF change completely. Relative and absolute CBF changes in the contralateral motor cortex are 53 ± 17% SD (n = 9) and 27 ± 11 SD ml/100 g/min (n = 9), respectively.     

Determination of arterial input function using fuzzy clustering for quantification of cerebral blood flow with dynamic susceptibility contrast-enhanced MR imaging

An accurate determination of the arterial input function (AIF) is necessary for quantification of cerebral blood flow (CBF) using dynamic susceptibility contrast-enhanced magnetic resonance imaging. In this study, we developed a method for obtaining the AIF automatically using fuzzy c-means (FCM) clustering. The validity of this approach was investigated with computer simulations. We found that this method can automatically extract the AIF, even under very noisy conditions, e.g., when the signal-to-noise ratio is 2. The simulation results also indicated that when using a manual drawing of a region of interest (ROI) (manual ROI method), the contamination of surrounding pixels (background) into ROI caused considerable overestimation of CBF. We applied this method to six subjects and compared it with the manual ROI method. The CBF values, calculated using the AIF obtained using the manual ROI method [CBF(manual)], were significantly higher than those obtained with FCM clustering [CBF(fuzzy)]. This may have been due to the contamination of non-arterial pixels into the manually drawn ROI, as suggested by simulation results. The ratio of CBF(manual) to CBF(fuzzy) ranged from 0.99-1.83 [1.31 +/- 0.26 (mean +/- SD)]. In conclusion, our FCM clustering method appears promising for determination of AIF because it allows automatic, rapid and accurate extraction of arterial pixels. J. Magn. Reson. Imaging 2001;13:797-806.     

Effects of blood flow modifiers on tumor metabolism observed in vivo by proton magnetic resonance spectroscopic imaging

Perfusion plays a key role in tumor proliferation and therapeutic response. Tumor heterogeneity necessitates use of the highest spatial resolution to monitor metabolic correlates of blood flow changes. This is best achieved with ¹H NMR spectroscopy, which permits noninvasive acquisition of high resolution spectroscopic images (SI) of subcutaneous tumors in a relatively short scan time (e.g., 12-25 μl voxels with signal-to-noise ratio 7:1 in 30 min at 4.7 T). This study seeks to identify ¹H spectroscopic indices of tumor blood flow. Proton SI of subcutaneous murine RIF-1 tumors were recorded (a) before and after administration of nicotinamide (1 g/kg) to increase blood flow, and (b) before and after hydralazine (10 mg/kg) to decrease flow. Nicotinamide produced a significant decrease in the total choline peak amplitudes, which subsequent high resolution NMR spectroscopy of tumor extracts revealed to be due to decreases in phosphocholine and glycerophosphocholine. The deamidation of nicotinamide to nicotinic acid, which is known to have hypolipidemic effects and to stimulate the formation of prostaglandins, may have sufficiently altered lipid metabolism to affect the in vivo concentration of the NMR-visible choline-containing compounds. The main effect of hydralazine was a significant increase of lactate, which is consistent with a reduction of tumor blood flow.     

Novel approach to the measurement of absolute cerebral blood volume using vascular-space-occupancy magnetic resonance imaging.

Quantitative determination of cerebral blood volume (CBV) is important for understanding brain physiology and pathophysiology. In this work, a novel approach is presented for accurate measurement of absolute CBV (aCBV) using vascular-space-occupancy (VASO) MRI, a blood-nulling pulse sequence, in combination with the T(1) shortening property of Gd-DTPA. Two VASO images with identical imaging parameters are acquired before and after contrast agent injection, resulting in a subtracted image that reflects the amount of blood present in the brain, i.e., CBV. With an additional normalizing factor, aCBV in units of milliliters of blood per 100 mL of brain can be estimated. Experimental results at 1.5 and 3 T systems showed that aCBV maps with high spatial resolution can be obtained with high reproducibility. The averaged aCBV values in gray and white matter were 5.5 +/- 0.2 and 1.4 +/- 0.1 mL of blood/100 mL of brain, respectively. Compared to dynamic susceptibility contrast techniques, VASO MRI is based upon a relatively straightforward theory and the calculation of CBV does not require measurement of an arterial input function. In comparison with previous pre/postcontrast difference approaches, VASO MRI provides maximal signal difference between pre- and postcontrast situation and does not require the use of whole blood for signal normalization.     

Cerebral T1rho relaxation time increases immediately upon global ischemia in the rat independently of blood glucose and anoxic depolarization.

Time-dependent changes of T1 in the rotating frame (T1rho), diffusion, T2, and magnetization transfer contrast on cardiac arrest-induced global ischemia in rat were investigated. T1rho, as acquired with spin lock amplitudes >0.6 G, started to increase 10-20 sec after cardiac arrest followed by an increase within 3-4 min to a level that was 6-8% greater than in normal brain. The ischemic T1rho response coincided with the drop of water diffusion coefficient in normoglycemic animals. However, unlike the rate of diffusion, the kinetics of T1rho were not affected by either preischemic hypoglycemia or hyperglycemia. Similar to diffusion, the kinetics of anoxic depolarization were dependent on preischemic blood glucose levels. Ischemia caused a reduction in the Hahn spin echo T2 as a result of blood oxygenation level-dependent (BOLD) effect; maximal negative BOLD seen by 40 sec. In the animals injected with an ironoxide particle contrast agent, AMI-227, prior to the insult, both T1rho and T2 immediately increased in concert on induction of ischemia. In contrast to the T1rho and diffusion changes, a much slower change in magnetization transfer contrast was evident over the first 20 min of ischemia. These data demonstrate that T1rho immediately increases following ischemia and that the pathophysiological mechanisms affecting this relaxation time may not directly involve magnetization transfer. The mechanisms prolonging T1rho differ from those affecting water diffusion with respect to their sensitivities to glucose and are apparently independent of membrane depolarization.     

Dynamic MRI sensitized to cerebral blood oxygenation and flow during sustained activation of human visual cortex

Changes in cerebral blood oxygenation and flow during prolonged activation of human visual cortex (6-min video projection) were monitored using high-resolution T₂*- and T₁-weighted gradient-echo MRI in identical sessions. Oxygenation-sensitive recordings displayed an initial signal increase (oxygenation “overshoot”), a subsequent signal decrease extending over 4–5 min (relative deoxygenation), and a signal drop after the end of stimulation that mirrored the initial response (oxygenation “undershoot”). How-senstive MRI demonstrated that the inflow effect remained elevated during the entire period of stimulation. The observation of gradually decreasing cerebral blood oxygenation, despite persisting elevation of blood flow, may be understood to be an accumulation of deoxyhemoglobin due to the progressive up-regulation of oxidative phosphorylation. The present findings support a concept in which transitions between functional states lead to an uncoupling of perfusion (oxygen delivery) from oxidative metabolism (oxygen consumption) whereas steady-state activfty achieves their recoupling.