Theoretical and experimental investigation of the VASO contrast mechanism.

Vascular space occupancy (VASO)-dependent functional MRI (fMRI) is a blood-nulling technique capable of generating microvascular cerebral blood volume (CBV)-weighted images. It is shown that at high magnetic field (3.0T) and high spatial resolution (1.89 x 1.89 x 3 mm(3)), the VASO signal changes are too large (6-7%) to originate from CBV effects alone. Additional contributions are investigated theoretically and experimentally as a function of MRI parameters (TR and TE), as well as the signal-to-noise ratio, (SNR) and spatial resolution. First, it is found that an arterial spin labeling (ASL) contribution causes large negative VASO signal changes at short TR. Second, even at high fMRI spatial resolution, CSF volume contributions (7-13%) cause VASO signal changes to become more negative, most noticeably at long TR and TE. Third, white matter (WM) effects reduce signal changes at lower spatial resolution. The VASO technique has been tested using different stimulus paradigms and field strengths (1-3), giving results consistent with comparable tasks investigated using BOLD and cerebral blood flow (CBF)-based techniques. Finally, simulations show that a mixture of fresh and steady-state blood may significantly alter signal changes at short TR (< or =3 s), permitting larger VASO signal changes than expected under pure steady-state conditions. Thus, many competing effects contribute to VASO contrast and care should be taken during interpretation.     

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.     

Applications and limitations of whole-brain MAGIC VASO functional imaging.

This work extends the multiple acquisitions with global inversion cycling vascular space occupancy (MAGIC VASO) method to human whole-brain functional magnetic resonance imaging (fMRI) at 3.0 Tesla and demonstrates the need to consider the dynamic contribution of cerebrospinal fluid (CSF) to the relative VASO signal change (DeltaVASO/VASO). Simulations were performed to determine the optimal slice number between global inversions, and correction factors were obtained to account for incomplete blood nulling in particular slices. The necessity of an accurate estimate of resting cerebral blood volume (CBV(rest)) is discussed in the context of DeltaCBV/CBV calculations. A three-compartment model is proposed to include both the resting and changing fractional CSF contribution (x(c,rest) and Deltax(c), respectively) to DeltaVASO/VASO. A MAGIC VASO sequence that provides whole-brain coverage is demonstrated using a paradigm comprised of visual, motor, and auditory stimulation. Activated regions are quantitatively compared in the corresponding blood oxygenation level-dependent (BOLD) images. Estimates of the minimum DeltaCBV/CBV resulting from motor and visual stimulation were comparable to previous findings at 17 +/- 8% (N = 8) and 19 +/- 9% (N = 6), respectively. The absence of VASO activation for auditory stimulation and evidence of activation-induced decreases in CSF volume fraction around the insula and superior temporal gyrus support the possibility of a Deltax(c) contribution to the VASO signal. Without specific knowledge of the CSF components (x(c,rest) and Deltax(c)), inference of DeltaCBV/CBV from DeltaVASO/VASO is severely limited.     

Functional imaging of the visual cortex with bold-contrast MRI: hyperventilation decreases signal response.

Hypocapnia due to hyperventilation reduces cerebral blood flow and volume. To investigate the effects of hyperventilation on the regional signal response to visual activation using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI), six volunteers were investigated during visual stimulation under normocapnia and hypocapnia conditions. Hyperventilation significantly decreased in visual cortex the BOLD MRI response to visual stimulation (3.97+/-0.5% [mean ( SD) in normocapnia vs. 0.77+/-0.7% in hypocapnia, P < 0.01]. In three of six subjects, functional signal changes were reduced to noise level. The reduced stimulus response during hyperventilation is probably due to a decreased overshoot in the blood oxygenation response. These results indicate that BOLD-contrast functional MRI is highly sensitive to pCO2 changes.     

Multiple acquisitions with global inversion cycling (MAGIC): a multislice technique for vascular-space-occupancy dependent fMRI.

Recently, a new fMRI technique, termed vascular-space-occupancy (VASO), was introduced that uses T1-based blood nulling to detect cerebral blood volume (CBV) changes during brain activity. However, similar to other T1-preparation methods, this technique is hampered by the fact that there is only one zero-crossing on the relaxation curve, presently limiting its application to single-slice studies. A multislice VASO-fMRI method is presented that employs a series of nonselective 180 degrees pulses to periodically invert the magnetization and maintain it around zero, while acquiring slices in between. The effects of magnetization transfer and signal contamination by stimulated echoes are discussed. Solutions to reduce the effect of T1-signal decay as a function of slice number are provided. Phantom data show excellent agreement between experiments and numerical simulations. Multislice VASO-fMRI images of visual stimulation show effective blood nulling in all slices and appropriate functional activations in all volunteers (n=4).     

CBF, BOLD, CBV, and CMRO(2) fMRI signal temporal dynamics at 500-msec resolution

PURPOSE: To investigate the temporal dynamics of blood oxygenation level-dependent (BOLD), cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO(2)) changes due to forepaw stimulation with 500-msec resolution in a single setting. MATERIALS AND METHODS: Forepaw stimulation and hypercapnic challenge on rats were studied. CBF and BOLD functional MRI (fMRI) were measured using the pseudo-continuous arterial spin-labeling technique at 500-msec resolution. CBV fMRI was measured using monocrystalline iron-oxide particles following CBF and BOLD measurements in the same animals. CMRO(2) change was estimated via the biophysical BOLD model with hypercapnic calibration. Percent changes and onset times were analyzed for the entire forepaw somatosensory cortices and three operationally defined cortical segments, denoted Layers I-III, IV-V, and VI. RESULTS: BOLD change was largest in Layers I-III, whereas CBF, CBV, and CMRO(2) changes were largest in Layers IV-V. Among all fMRI signals in all layers, only the BOLD signal in Layers I-III showed a poststimulus undershoot. CBF and CBV dynamics were similar. Closer inspection showed that CBV increased slightly first (P < 0.05), but was slow to peak. CBF increased second, but peaked first. BOLD significantly lagged both CBF and CBV (P < 0.05). CONCLUSION: This study provides important temporal dynamics of multiple fMRI signals at high temporal resolution in a single setting.     

Simultaneous MRI acquisition of blood volume, blood flow, and blood oxygenation information during brain activation.

Simultaneous acquisition of complementary functional hemodynamic indices reflecting different aspects of brain activity would be a valuable tool for functional brain-imaging studies offering enhanced detection power and improved data interpretation. As such, a new MRI technique is presented that is able to achieve concurrent acquisition of three hemodynamic images based primarily on the changes of cerebral blood volume, blood flow, and blood oxygenation, respectively, associated with brain activation. Specifically, an inversion recovery pulse sequence has been designed to measure VASO (vascular space occupancy), ASL (arterial spin labeling) perfusion, and BOLD (blood-oxygenation-level-dependent) signals in a single scan. The MR signal characteristics in this sequence were analyzed, and image parameters were optimized for the simultaneous acquisition of these functional images. The feasibility and efficacy of the new technique were assessed by brain activation experiments with visual stimulation paradigms. Experiments on healthy volunteers showed that this technique provided efficient image acquisition, and thus higher contrast-to-noise ratio per unit time, compared with conventional techniques collecting these functional images separately. In addition, it was demonstrated that the proposed technique was able to be utilized in event-related functional MRI experiments, with potential advantages of obtaining accurate transient information of the activation-induced hemodynamic responses.     

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.     

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

Although BOLD functional MRI (fMRI) provides a useful tool for probing neuronal activities, large intersubject variations in signal amplitude are commonly observed. Understanding the physiologic basis for these variations will have a significant impact on many fMRI studies. First, the physiologic modulator can be used as a regressor to reduce variations across subjects, thereby improving statistical power for detecting group differences. Second, if a pathologic condition or a drug treatment is shown to change fMRI responses, monitoring this modulatory parameter is useful in correctly interpreting the fMRI changes to neuronal deficits/recruitments. Here we present evidence that the task‐evoked fMRI signals are modulated by baseline blood oxygenation. To measure global blood oxygenation, we used a recently developed technique, T₂ relaxation under spin‐tagging (TRUST) MRI, which yielded baseline oxygenation of 63.7% ± 7.2% in the sagittal sinus with an estimation error of 1.3%. It was found that individuals with higher baseline oxygenation tend to have a smaller fMRI signal, and vice versa. For every 10% difference in baseline oxygenation across subjects, BOLD and cerebral blood flow (CBF) signals differ by –0.4% and –30.0%, respectively, when using visual stimulation. TRUST MRI is a useful measurement for fMRI studies to control for the modulatory effects of baseline oxygenation that are unique to each subject. Magn Reson Med 60:364–372, 2008. © 2008 Wiley‐Liss, Inc.     

Implementation of vascular‐space‐occupancy MRI at 7T

Vascular‐space‐occupancy (VASO) MRI exploits the difference between blood and tissue T₁ to null blood signal and measure cerebral blood volume changes using the residual tissue signal. VASO imaging is more difficult at higher field because of sensitivity loss due to the convergence of tissue and blood T₁ values and increased contamination from blood‐oxygenation‐level‐dependent (BOLD) effects. In addition, compared to 3T, 7T MRI suffers from increased geometrical distortions, e.g., when using echo‐planar‐imaging, and from increased power deposition, the latter especially problematic for the spin‐echo‐train sequences commonly used for VASO MRI. Third, non‐steady‐state blood spin effects become substantial at 7T when only a head coil is available for radiofrequency transmit. In this study, the magnetization‐transfer‐enhanced‐VASO approach was applied to maximize tissue‐blood signal difference, which boosted signal‐to‐noise ratio by 149% ± 13% (n = 7) compared to VASO. Second, a 3D fast gradient‐echo sequence with low flip‐angle (7°) and short echo‐time (1.8 ms) was used to minimize the BOLD effect and to reduce image distortion and power deposition. Finally, a magnetization‐reset technique was combined with a motion‐sensitized‐driven‐equilibrium approach to suppress three types of non‐steady‐state spins. Our initial functional MRI results in normal human brains at 7T with this optimized VASO sequence showed better signal‐to‐noise ratio than at 3T. Magn Reson Med 69:1003–1013, 2013. © 2012 Wiley Periodicals, Inc.     

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.     

Pharmacological modulation of the BOLD response: a study of acetazolamide and glyceryl trinitrate in humans

Purpose:

To examine the effect of acetazolamide, known to increase cerebral blood flow (CBF) and glyceryl trinitrate (GTN), known to increase cerebral blood volume (CBV) on the blood oxygenation level‐dependent (BOLD) response in humans using 3 T magnetic resonance imaging (MRI), and to evaluate how pharmacological agents may modulate cerebral hemodynamic and thereby possibly the BOLD signal.

Materials and Methods:

Six subjects were randomly allocated to receive acetazolamide, GTN, or placebo in a double‐blind three‐way crossover controlled study. Before, during, and after drug administration we recorded the BOLD response during visual stimulation with reversing checkerboard.

Results:

We found that acetazolamide caused significant depression of the BOLD response (P = 0.0066). The maximum decrease occurred at 5 minutes after infusion and was 51.9% (95% confidence interval [CI], 22.03–81.76). GTN did not influence the BOLD response (P = 0.55).

Conclusion:

The BOLD response is decreased during increased CBF by acetazolamide, suggesting an inverse relationship between global CBF and the BOLD response. GTN does not change the BOLD response. This indicates that GTN exerts an effect on the large vessels only and that CBV changes in the microvascular system are necessary to alter the BOLD response. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.     

Venous refocusing for volume estimation: VERVE functional magnetic resonance imaging.

A novel, noninvasive magnetic resonance imaging-based method for measuring changes in venous cerebral blood volume (CBV(v)) is presented. Venous refocusing for volume estimation (VERVE) exploits the dependency of the spin-spin relaxation rate of deoxygenated blood on the refocusing interval. Interleaved CPMG EPI acquisitions following a train of either tightly or sparsely spaced hard refocusing pulses (every 3.7 or 30 msec, respectively) at matched echo time were used to isolate the blood signal while minimizing the intravascular blood oxygenation level dependent (BOLD) signal contribution. The technique was employed to determine the steady-state increase in the CBV(v) in the visual cortex (VC) in seven healthy adult volunteers during flickering checkerboard photic stimulation. A functional activation model and a set of previously collected in vitro human whole blood relaxometry data were used to evaluate the intravascular BOLD effect on the VERVE signal. The average VC venous blood volume change was estimated to be 16 +/- 2%. This method has the potential to provide efficient and continuous monitoring of venous cerebral blood volume, thereby enabling further exploration of the mechanism underlying BOLD signal changes upon physiologic, pathophysiologic, and pharmacologic perturbations.     

Dynamic characteristics of oxygenation-sensitive MRI signal in different temporal protocols for imaging human brain activity

The temporal characteristics of cerebral blood oxygenation during human brain activation were monitored with dynamic echo-planar imaging (EPI) using the blood oxygenation level dependent (BOLD) fMRI. We investigated oxygenation-sensitive signal changes: 1. during repetitive block stimuli, to determine the latency of the activation-induced signal change in the primary visual cortex; 2. on shortening the rest periods between constant stimulated phases, to investigate the limitations that this latency poses in temporal resolution of the technique; and 3. on sustained steady-state stimulation, to characterise oxygenation changes during prolonged brain activation using different stimuli. Delayed intrinsic haemodynamic response and a finite signal-to-noise ratio limit the temporal resolution achieved with BOLD fMRI. Separate activation periods were resolved when the delay between consecutive stimulations was at least 2 s. In this study oxygenation remained elevated throughout sustained activation, suggesting a constant rate of oxygen consumption by the primary cortical neurones during activation. Characterisation of fMRI signal dynamics in dynamic temporal protocols is significant both in terms of optimising stimulation protocols and the potential to gain insight into the physiological mechanisms underlying neuronal activation which could increase the clinical applicability of the technique. Received: 13 September 1999 Accepted: 10 November 1999     

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.     

Oxygenation and hematocrit dependence of transverse relaxation rates of blood at 3T.

Knowledge of the transverse relaxation rates R2 and R2* of blood is relevant for quantitative assessment of functional MRI (fMRI) results, including calibration of blood oxygenation and measurement of tissue oxygen extraction fractions (OEFs). In a temperature controlled circulation system, these rates were measured for blood in vitro at 3T under conditions akin to the physiological state. Single spin echo (SE) and gradient echo (GRE) sequences were used to determine R2 and R2*, respectively. Both rates varied quadratically with deoxygenation, and changes in R2* were found to be due predominantly to changes in R2. These data were used to estimate intravascular blood oxygenation level dependent (BOLD) contributions during visual activation. Due to the large R2* in venous blood, intravascular SE BOLD signal changes were larger than GRE effects at echo times above 30 ms. When including extravascular effects to estimate the total BOLD effect, GRE BOLD dominated due to the large tissue volume fraction.     

Anesthetic effects on regional CBF,BOLD, and the coupling between task‐induced changes in CBF and BOLD: An fMRI study in normal human subjects

Functional MR imaging was performed in sixteen healthy human subjects measuring both regional cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) signal when visual and auditory stimuli were presented to subjects in the presence or absence of anesthesia. During anesthesia, 0.25 mean alveolar concentration (MAC) sevoflurane was administrated. We found that low‐dose sevoflurane decreased the task‐induced changes in both BOLD and CBF. Within the visual and auditory regions of interest inspected, both baseline CBF and the task‐induced changes in CBF decreased significantly during anesthesia. Low‐dose sevoflurane significantly altered the task‐induced CBF‐BOLD coupling; for a unit change of CBF, a larger change in BOLD was observed in the anesthesia condition than in the anesthesia‐free condition. Low‐dose sevoflurane was also found to have significant impact on the spatial nonuniformity of the task‐induced coupling. The alteration of task‐induced CBF‐BOLD coupling by low‐dose sevoflurane introduces ambiguity to the direct interpretation of functional MRI (fMRI) data based on only one of the indirect measures—CBF or BOLD. Our observations also indicate that the manipulation of the brain with an anesthetic agent complicates the model‐based quantitative interpretation of fMRI data, in which the relative task‐induced changes in oxidative metabolism are calculated by means of a calibrated model given the relative changes in the indirect vascular measures, usually CBF and BOLD. Magn Reson Med 60:987–996, 2008. © 2008 Wiley‐Liss, Inc.     

Relationship between caffeine-induced changes in resting cerebral perfusion and blood oxygenation level-dependent signal

BACKGROUND AND PURPOSE: Recent interest has emerged in the use of pharmacologic methods to maximize blood oxygenation level-dependent (BOLD) signal intensity changes in functional MR imaging (fMRI). Adenosine antagonists, such as caffeine and theophylline, have been identified as potential agents for this purpose. The present study was designed to determine whether caffeine-induced decreases in cerebral perfusion result in enhanced BOLD responses to visual and auditory stimuli. METHODS: MR imaging was used to measure resting cerebral perfusion and stimulus-induced BOLD signal intensity changes in 19 patients. We evaluated the relationship between resting cerebral perfusion and the magnitude of BOLD signal intensity induced by visual and auditory stimulation under caffeine and placebo conditions. RESULTS: The data showed that changes in resting cerebral perfusion produced by caffeine are not a consistent predictor of BOLD signal intensity magnitude. Although all cerebral perfusion was reduced in all study participants in response to caffeine, only 47% of the participants experienced BOLD signal intensity increase. This finding was independent of the participants' usual caffeine consumption. CONCLUSION: The data presented herein show that the relationship between resting cerebral perfusion and the magnitude of BOLD signal intensity is complex. It is not possible to consistently enhance BOLD signal intensity magnitude by decreasing resting perfusion with caffeine. Future studies aimed at evaluating the relationship between perfusion and BOLD signal intensity changes should seek a means to selectively modulate known components of the neural and vascular responses independently.     

Magnetization transfer enhanced vascular‐space‐occupancy (MT‐VASO) functional MRI

Vascular‐space‐occupancy (VASO) MRI is a novel technique that uses blood signal nulling to detect blood volume alterations through changes in tissue signal. VASO has relatively low signal to noise ratio (SNR) because only 10–20% of tissue signal remain at the time of blood nulling. Here, it is shown that by adding a magnetization transfer (MT) prepulse it is possible to increase SNR either by attenuating the initial tissue magnetization when the MT pulse is placed before inversion, or, accelerating the recovery process when the pulse is applied after the inversion. To test whether the MT pulse would affect the blood nulling time in VASO, MT effects in blood were measured both ex vivo in a bovine blood phantom and in vivo in human brain. Such effects were found to be sufficiently small (< 2.5%) under a saturation power ≤ 3 μT, length = 500 ms, and frequency offset ≥40 ppm to allow use of the same nulling time. Subsequently, functional MRI experiments using MT‐VASO were performed in human visual cortex at 3 Tesla. The relative signal changes in MT‐VASO were of the same magnitude as in VASO, while the contrast to noise ratio (CNR) was enhanced by 44 ± 12% and 36 ± 11% respectively. Therefore, MT‐VASO should provide a means for increasing inherently low CNR in VASO experiments while preserving the CBV sensitivity. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

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.