Simultaneous perfusion and blood-oxygenation-level-dependent measurements using single-shot interleaved z-shim echo-planar imaging.

Single-shot interleaved z-shim EPI (SSIZS-EPI) was extended to a simultaneous perfusion and blood-oxygenation-level-dependent (BOLD) imaging technique that reduces susceptibility-induced signal loss while preserving rapid image acquisition. Experiments on human brains showed that images acquired with this technique had improved signal-to-noise ratio in the inferior prefrontal, meso-, and lateral-temporal lobes compared with a conventional EPI. Perfusion maps obtained from the SSIZS-EPI images at resting state illustrated substantial signal recovery in these brain areas. Perfusion and BOLD images collected with a sensorimotor paradigm demonstrated the feasibility of the technique to simultaneously measure cerebral blood flow and blood oxygenation signals associated with brain activation. Functional experiments with a neuropsychiatric paradigm showed increased brain activities in the periamygdalar regions in both perfusion and BOLD maps, consistent with a previous H(2) (15)O PET study. The proposed technique, with its advantages of reducing susceptibility artifacts and fast scanning speed, would be useful for obtaining more reliable measurements of functional signals, particularly in the brain regions with field inhomogeneities.     

Quantification of arterial cerebral blood volume using multiphase-balanced SSFP-based ASL

A new technique is introduced in this study for in vivo measurement of arterial cerebral blood volume by combining arterial spin labeling with a segmented multiphase balanced steady-state free precession (bSSFP) readout sequence. This technique takes advantage of the phenomenon that the longitudinal magnetization of flowing blood is not or only marginally disturbed (besides T(1) relaxation) by the bSSFP ± α pulse train. When the blood water exchanges into tissue, it becomes quickly saturated by the bSSFP pulse train due to 0 velocity and reduced T(1), T(2) relaxation times. Therefore, labeled blood water behaves like an intravascular contrast agent in multiphase bSSFP scans, and can be used to quantify arterial cerebral blood volume in a similar way as dynamic susceptibility contrast MRI. Both Bloch equation simulation and in vivo experiments were carried out to demonstrate the feasibility for quantifying cerebral blood volume in arteries, arterioles, and capillaries using two variants of the proposed method. Functional MRI of visual cortex stimulation was further performed using multiphase bSSFP-based arterial spin labeling and compared with vascular-space occupancy contrast. The proposed multiphase bSSFP-based arterial spin labeling technique may allow separation of cerebral blood volume of different vascular compartments for functional MRI studies and clinical evaluation of the cerebral vasculature.     

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.     

BOLD and CBV-weighted functional magnetic resonance imaging of the rat somatosensory system.

A multislice spin echo EPI sequence was used to obtain functional MR images of the entire rat brain with blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) contrast at 11.7 T. Maps of activation incidence were created by warping each image to the Paxinos rat brain atlas and marking the extent of the activated area. Incidence maps for BOLD and CBV were similar, but activation in draining veins was more prominent in the BOLD images than in the CBV images. Cerebellar activation was observed along the surface in BOLD images, but in deeper regions in the CBV images. Both effects may be explained by increased signal dropout and distortion in the EPI images after administration of the ferumoxtran-10 contrast agent for CBV fMRI. CBV-weighted incidence maps were also created for 10, 20, and 30 mg Fe/kg doses of ferumoxtran-10. The magnitude of the average percentage change during stimulation increased from 4.9% with the 10 mg Fe/kg dose to 8.7% with the 30-mg Fe/kg dose. Incidence of activation followed a similar trend.     

Dynamics of blood flow and oxygenation changes during brain activation: The balloon model

A biomechanical model is presented for the dynamic changes in deoxyhemoglobin content during brain activation. The model incorporates the conflicting effects of dynamic changes in both blood oxygenation and blood volume. Calculations based on the model show pronounced transients in the deoxyhemoglobin content and the blood oxygenation level dependent (BOLD) signal measured with functional MRI, including initial dips and overshoots and a prolonged post-stimulus undershoot of the BOLD signal. Furthermore, these transient effects can occur in the presence of tight coupling of cerebral blood flow and oxygen metabolism throughout the activation period. An initial test of the model against experimental measurements of flow and BOLD changes during a finger-tapping task showed good agreement.     

Application of selective saturation to image the dynamics of arterial blood flow during brain activation using magnetic resonance imaging.

A saturation-based approach is proposed to image the arterial blood flow signal with temporal resolution of 1 to 2 s and in-plane spatial resolution of a few millimeters. Using a saturation approach to suppress the undesired background stationary signal allows the blood water that enters the slice to be imaged at some specified later time. Since the blood protons that are being imaged are not restricted to the intravascular space, this technique is also sensitive to tissue perfusion signal contributions. The signal uptake characteristics of the saturation method proposed were used to study the different signal contributions as a function of the acquisition parameters. A typical perfusion acquisition (FAIR) was also used for comparison. The proposed method was demonstrated in a functional motor activation experiment and the observed signal changes were smaller than those obtained using the FAIR acquisition. The dynamics of the saturation method and FAIR temporal signal changes were investigated and time constants between 2 and 44 s were estimated. The tissue signal contribution to the saturation method's signal was small over the range of acquisition parameters that sensitized it to the arterial compartment.     

Vascular space occupancy-dependent functional MRI by tissue suppression

PURPOSE: To measure the cerebral blood volume (CBV) dynamics during neural activation, a novel technique named vascular space occupancy (VASO)-based functional MRI (fMRI) was recently introduced for noninvasive CBV detection. However, its application is limited because of its low contrast-to-noise ratio (CNR) due to small signal change from the inverted blood. MATERIALS AND METHODS: In this study a new approach-VASO with tissue suppression (VAST)-is proposed to enhance CNR. This technique is compared with VASO and blood oxygenation level-dependent (BOLD) fMRI in block-design and event-related visual experiments. RESULTS: Based on acquired T(1) maps, 75.3% of the activated pixels detected by VAST are located in the cortical gray matter. Temporal characteristics of functional responses obtained by VAST were consistent with that of VASO. Although the baseline signal was decreased by the tissue suppression, the CNR of VAST was about 43% higher than VASO. CONCLUSION: With the improved sensitivity, VAST fMRI provides a useful alternative for mapping the spatial/temporal features of regional CBV changes during brain activation. However, the technical imperfectness of VAST, such as the nonideal inversion efficiency and physiological contaminations, limits its application to precise CBV quantification.     

Localized echo-volume imaging methods for functional MRI

To perform true three-dimensional activation experiments in the human brain, dedicated localized echo-volume imaging (L-EVI) methods were developed. Three-dimensional acquisition allows generation of activation maps with minimal vascular enhancement related to inflow effects. The rapid acquisition of the L-EVI (～100 msec) reduces signal instabilities caused by motion, facilitating the detection of the small intensity changes expected with brain activation. Single-shot L-EVI was performed on normal volunteers at 1.5 T, imaging a three-dimensional predefined volume (240 × 45 × 45 mm³) in the superior portion of the brain with a spatial resolution of 3.75 × 5 × 5 mm³. Increased brain coverage was achieved with a multi-volume imaging (three-shot) version, which simultaneously achieved effective suppression of signals from cerebrospinal fluid. In addition, both asymmetric spin-echo (ASE) and spin-echo (SE) versions of the technique were used to detect blood oxygenation level dependent (BOLD) signal changes in the motor cortex with a finger-tapping paradigm. Images obtained by the L-EVI sequence were qualitatively comparable to standard multislice two-dimensional echo-planar images. Both ASE and SE functional MRI (fMRI) experiments showed consistent activation in the contralateral primary sensorimotor cortex. Furthermore, significant differences in location and magnitude of activation was observed between the two methods, confirming theoretical predictions.     

Perfusion-weighted imaging of interictal hypoperfusion in temporal lobe epilepsy using FAIR-HASTE: comparison with H(2)(15)O PET measurements.

To detect perfusion abnormalities in areas of high magnetic susceptibility in the brain, an arterial spin-labeling MRI technique utilizing flow-sensitive alternating inversion recovery (FAIR) and half-Fourier single shot turbo spin-echo (HASTE) for spin preparation and image acquisition, respectively, was developed. It was initially tested in a functional study involving visual stimulation, and was able to detect significant activation with an increase (approximately 70%) in relative cerebral blood flow. Subsequently, it was applied in a clinical situation in eight patients with temporal lobe epilepsy (TLE). The perfusion-weighted images obtained showed no susceptibility artifacts even in the region of the inferior temporal lobe and were able to detect interictal hypoperfusion in TLE. The results were compared with those derived from H(2)(15)O PET perfusion imaging in each patient. A statistically significant correlation (r = 0.75, P < 0.05) was found between results acquired from these two modalities. Magn Reson Med 45:431-435, 2001.     

Detrimental effects of BOLD signal in arterial spin labeling fMRI at high field strength.

Arterial spin labeling (ASL) MRI is a useful technique for noninvasive measurement of cerebral blood flow (CBF) in humans. High field strength provides a unique advantage for ASL because of longer blood T(1) relaxation times, making this technique a promising quantitative approach for functional brain mapping. However, higher magnetic field also introduces new challenges. Here it is shown that the CBF response determined using ASL functional MRI (fMRI) at 3.0 T contains significant contamination from blood-oxygenation-level-dependent (BOLD) effects. Due to interleaved acquisitions of label and control images, difference in blood oxygenation status between these two scans can cause incomplete cancellation of the static signal upon image subtraction, resulting in a BOLD-related artifact in the estimated CBF hemodynamics. If not accounted for, such an effect can complicate the interpretation of the ASL results, e.g., causing a delayed onset and offset of the response, or inducing an artifactual poststimulus undershoot. The BOLD contribution also decreases the sensitivity of ASL-based fMRI. Correction methods are proposed to reduce the artifact, giving increased number of activated voxels (18+/-5%, P=0.006) and more accurate estimation of CBF temporal characteristics.     

Functional MRI using steady-state arterial water labeling

Flow-sensitive functional MRI (fMRI) was performed using steady-state arterial water labeling (SS-AWL). Arterial water labeling was accomplished by flow induced adiabatic fast passage. The signal intensity of the visual cortex in arterial water labeled images decreased by ?1.4% during visual stimulation of the brain. Acquisition of arterial water unlabeled and labeled images allows measurement of relative cerebral blood flow increase during brain activation. During visual stimulation, cerebral blood flow in the visual cortex increased by 17 to 35% as measured by SS-AWL. Quantitation of brain activation in terms of a physiological parameter using SS-AWL will facilitate comparative fMRI studies under different conditions.     

Comparison of TCA and ICA techniques in fMRI data processing

PURPOSE: To make a quantitative comparison of temporal cluster analysis (TCA) and independent component analysis (ICA) techniques in detecting brain activation by using simulated data and in vivo event-related functional MRI (fMRI) experiments. MATERIALS AND METHODS: A single-slice MRI image was replicated 150 times to simulate an fMRI time series. An event-related brain activation pattern with five different levels of intensity and Gaussian noise was superimposed on these images. Maximum contrast-to-noise ratio (CNR) of the signal change ranged from 1.0 to 2.0 by 0.25 increments. In vivo visual stimulation fMRI experiments were performed on a 1.9 T magnet. Six human volunteers participated in this study. All imaging data were analyzed using both TCA and ICA methods. RESULTS: Both simulated and in vivo data have shown that no statistically significant difference exists in the activation areas detected by both ICA and TCA techniques when CNR of fMRI signal is larger than 1.75. CONCLUSION: TCA and ICA techniques are comparable in generating functional brain maps in event-related fMRI experiments. Although ICA has richer features in exploring the spatial and temporal information of the functional images, the TCA method has advantages in its computational efficiency, repeatability, and readiness to average data from group subjects     

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.     

Estimating cerebral blood volume with expanded vascular space occupancy slice coverage

A model for quantifying cerebral blood volume (CBV) based on the vascular space occupancy (VASO) technique and varying the extent of blood nulling yielding task‐related signal changes with various amounts of blood oxygenation level‐dependent (BOLD) and VASO weightings was previously described. Challenges associated with VASO include limited slice coverage and the confounding inflow of fresh blood. In this work, an approach that extends the previous model to multiple slices and accounts for the inflow effect is described and applied to data from a multiecho sequence simultaneously acquiring VASO, cerebral blood flow (CBF), and BOLD images. This method led to CBV values (7.9 ± 0.3 and 5.6 ± 0.3 ml blood/100 ml brain during activation [CBV_ACT] and rest [CBV_REST], respectively) consistent with previous studies using similar visual stimuli. Furthermore, an increase in effective blood relaxation (0.65 ± 0.01) compared to the published value (0.62) was detected, likely reflecting inflow of fresh blood. Finally, cerebral metabolic rate of oxygen (CMRO₂) estimates using a multiple compartment model without assumption of CBV_REST led to estimates (18.7 ± 17.0%) that were within published ranges. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Simultaneous noninvasive measurement of CBF and CBV using double-echo FAIR (DEFAIR).

A new method for measuring cerebral blood flow (CBF) and cerebral blood volume (CBV) noninvasively using MRI is presented. The approach is based on the technique of arterial spin labelling (ASL), in which CBF-based contrast is generated by controlled modulation of the longitudinal magnetization of the blood. The proposed method also uses differences in T(2) between tissue and blood to differentiate the two compartments and allow assessment of the relative size of each. Two successive EPI images are acquired following spin preparation using either a slice-selective or global inversion pulse, and the technique is therefore referred to as double-echo FAIR (DEFAIR). DEFAIR is demonstrated in the normal gerbil brain and during hypothermia, where reductions of both CBF and CBV are known to occur. It is also shown theoretically that this method can be extended to include a measurement of oxygen extraction fraction. The main drawbacks of the technique are the long acquisition time and relatively low sensitivity to hemodynamic changes compared to conventional qualitative T2(*)-weighted BOLD contrast, which may limit its applicability and practical use in monitoring functional cerebral activation. However, the technique can be used repetitively in longer-term time course studies due to its noninvasive and quantitative nature.     

Modulation of cerebral blood oxygenation by indomethacin: MRI at rest and functional brain activation

The modulation of blood oxygenation level-dependent (BOLD) cerebral MRI contrast by the vasoconstrictive drug indomethacin (i.v. 0.2 mg/kg b.w.) was investigated in 10 healthy young adults without and with functional challenge (repetitive and sustained visual activation). For comparison, isotonic saline (placebo, 20 mL) and acetylsalicylate (i.v. 500 mg) were investigated as well, each in separate sessions using identical protocols. After indomethacin, dynamic T2*-weighted echo-planar MRI at 2.0 T revealed a rapid decrease in MRI signal intensity by 2.1%-2.6% in different gray matter regions (P < or = 0.001 compared to placebo), which was not observed for acetylsalicylate and the placebo condition. Regional signal differences were not significant within gray matter, but all gray matter regions differed significantly from the signal decrease of only 1.2% +/- 0.7% observed in white matter (P = 0.001). For the experimental parameters used, a 1% MRI signal decrease in response to indomethacin was estimated to correlate with a decrease of the cerebral blood flow by about 12 ml/100 g/minute, and an increase of the oxygen extraction fraction by about 15%. Responses to visual activation were not affected by saline or acetylsalicylate, and yielded 5.0%-5.5% BOLD MRI signal increases both before and after drug application. In contrast, indomethacin reduced the initial response strength to 82%-85% of that obtained without the drug. The steady-state response during sustained activation reached only 47% of the corresponding pre-drug level (P < 0.01). During repetitive activation the BOLD contrast was reduced to 66% of that observed for control conditions (P < 0.001). In conclusion, indomethacin attenuates the vasodilatory force at functional brain activation, indicating different mechanisms governing neurovascular coupling.     

Quantitative measurements of cerebral blood flow in rats using the FAIR technique: Correlation with previous lodoantipyrine autoradiographic studies

Flow-sensitive alternating inversion recovery (FAIR) is a recently introduced MRI technique for assessment of perfusion that uses blood water as an endogenous contrast agent. To characterize the FAIR signal dependency on spin tagging time (inversion time (Tl)) and to validate FAIR for cerebral blood flow (CBF) quantification, studies were conducted on the rat brain at 9.4 T using a conventional gradient-recalled echo sequence. The 7¹, of cerebral cortex and blood was found to be 1.9 and 2.2 s, respectively, and was used for CBF calculations. At short Tls (<0.8 s), the FAIR signal originates largely from vascular components with fast flows, resulting in an overestimation of CBF. For Tl > 1.5 s, the CBF calculated from FAIR is independent of the spin tagging time, suggesting that the observed FAIR signal originates predominantly from tissue/capillary components. CBF values measured by FAIR with Tl of 2.0 s were found to be in good agreement with those measured by the iodoantipyrine technique with autoradiogra-phy in rats under the same conditions of anesthesia and arterial pCO₂. The measured pCO₂ index on the parietal cortex using the FAIR technique was 6.07 ml/100 g/min per mmHg, which compares well with the pCO₂ index measured by other techniques. The FAIR technique was also able to detect the regional reduction in CBF produced by middle cerebral artery occlusion in rats.     

T1rho contrast in functional magnetic resonance imaging.

The application of T1 in the rotating frame (T1rho) to functional MRI in humans was studied at 3 T. Increases in neural activity increased parenchymal T1rho. Modeling suggested that cerebral blood volume mediated this increase. A pulse sequence named spin-locked echo planar imaging (SLEPI) that produces both T1rho and T2* contrast was developed and used in a visual functional MRI (fMRI)experiment. Spin-locked contrast significantly augments the T2* blood oxygen level-dependent (BOLD) contrast in this sequence. The total functional contrast generated by the SLEPI sequence (1.31%) was 54% larger than the contrast (0.85%) obtained from a conventional gradient-echo EPI sequence using echo times of 30 ms. Analysis of image SNR revealed that the spin-locked preparation period of the sequence produced negligible signal loss from static dephasing effects. The SLEPI sequence appears to be an attractive alternative to conventional BOLD fMRI, particularly when long echo times are undesirable, such as when studying prefrontal cortex or ventral regions, where static susceptibility gradients often degrade T2*-weighted images.     

Multi-Slice MRI of Rat Brain Perfusion During Amphetamine Stimulation Using Arterial Spin Labeling

When a single coil is used to measure perfusion by arterial spin labeling, saturation of macromolecular protons occurs during the labeling period. Induced magnetization transfer contrast (MTC) effects decrease tissue water signal intensity, reducing the sensitivity of the technique. In addition, MTC effects must be properly accounted for in acquiring a control image. This forces the image to a single slice centered between the labeling plane and the control plane. In this work, a two-coil system is presented as a way to avoid saturation of macromolecular spins during arterial spin labeling. The system consists of one small surface coil for labeling the arterial water spins, and a head coil for MRI, actively decoupled from the labeling coil by using PIN diodes. It is shown that no signal loss occurs due to MTC effects when the two-coil system is used for MRI of rat brain perfusion, enabling three-dimensional perfusion imaging. Using the two-coil system, a multi-slice MRI sequence was used to study the regional effects of amphetamine on brain perfusion. Amphetamine causes significant increases in perfusion in many areas of the brain including the cortex, cingulate, and caudate putamen, in agreement with previous results using deoxyglucose uptake to monitor brain activation.     

Functional magnetic resonance: new applications in epilepsy

Functional magnetic resonance imaging technique is a non-invasive tool that is capable to detect the subtle hemodynamic changes produced during regional brain activation. Functional MRI applications in epilepsy patients are language lateralization and mapping, memory function assessment and localization of ictal and interictal changes. Functional MRI for language lateralization is currently used in clinical practice and provides comparable results to the intracarotid amobarbital test. In functional MRI studies for memory function assessment, results show changes in epileptic patients, but further studies are required to validate this technique for individual cases. A new application is ictal or interictal functional MRI with EEG recording that provides more detailed information about simultaneous electrographic and hemodynamic changes during interictal discharges or EEG seizures. This technique seems to have encouraging results to localize the epileptogenic area and to study propagation patterns.