Sources of functional apparent diffusion coefficient changes investigated by diffusion-weighted spin-echo fMRI.

The mechanism behind previously observed changes in the apparent diffusion coefficient (ADC) during brain activation is not well understood. Therefore, we investigated the signal source and spatial specificity of functional magnetic resonance imaging (fMRI) ADC changes systematically in the visual cortex of cats using diffusion-weighted (DW) spin-echo (SE) fMRI with b-values of 2, 200, and 800 s/mm(2), and echo times (TE) of 16, 28, and 60 ms at 9.4 T. For b > or = 200 s/mm(2), no ADC changes were detected in brain parenchyma, suggesting a minimal tissue contribution to the ADC change. For b < or = 200 s/mm(2), TE-dependent ADC increases were observed. When the venous blood contribution was minimized, the ADC change was higher at the middle cortical layer than at the cortical surface, which is mainly attributed to a functional elevation in arterial blood volume. At TE = 16 ms, the highest ADC changes occurred at the cortical surface with its large draining veins, which can mainly be explained by an additional contribution from the venous blood oxygenation changes. Our TE-dependent ADC results agree with computer simulations based on a three-compartment model. The contribution of arterial blood volume changes in ADC fMRI offers an improvement in spatial localization for SE-BOLD fMRI studies.     

Quantifying the spatial resolution of the gradient echo and spin echo BOLD response at 3 Tesla.

The blood oxygen level dependent (BOLD) response, as measured with fMRI, offers good spatial resolution compared to other non-invasive neuroimaging methods. The use of a spin echo technique rather than the conventional gradient echo technique may further improve the resolution by refocusing static dephasing effects around the larger vessels, so sensitizing the signal to the microvasculature. In this work the width of the point spread function (PSF) of the BOLD response at a field strength of 3 Tesla is compared for these two approaches. A double echo EPI pulse sequence with simultaneous collection of gradient echo and spin echo signal allows a direct comparison of the techniques. Rotating multiple-wedge stimuli of different spatial frequencies are used to estimate the width of the BOLD response. Waves of activation are created on the surface of the visual cortex, which begin to overlap as the wedge separation decreases. The modulation of the BOLD response decreases with increasing spatial frequency in a manner dependent on its width. The spin echo response shows a 13% reduction in the width of the PSF, but at a cost of at least 3-fold reduction in contrast to noise ratio.     

High-resolution, spin-echo BOLD, and CBF fMRI at 4 and 7 T.

With growing interest in noninvasive mapping of columnar organization and other small functional structures in the brain, achieving high spatial resolution and specificity in fMRI is of critical importance. We implemented a simple method for BOLD and perfusion fMRI with high spatial resolution and specificity. Increased spatial resolution was achieved by selectively exciting a slab of interest along the phase-encoding direction for EPI, resulting in a reduced FOV and number of phase-encoding steps. Improved spatial specificity was achieved by using SE EPI acquisition at high fields, where it is predominantly sensitive to signal changes in the microvasculature. Robust SE BOLD and perfusion fMRI were obtained with a nominal in-plane resolution up to 0.5 x 0.5 mm(2) at 7 and 4 Tesla, and were highly reproducible under repeated measures. This methodology enables high-resolution and high-specificity studies of functional topography in the millimeter to submillimeter spatial scales of the human brain.     

Effect of graded hypo- and hypercapnia on fMRI contrast in visual cortex: quantification of T(*)(2) changes by multiecho EPI.

The sensitivity of functional magnetic resonance imaging (fMRI) in visual cortex to graded hypo- and hypercapnia was quantified in 10 normal subjects using single-shot multiecho echo-planar imaging (Turbo-PEPSI) with eight equidistant echo times (TEs) between 12 and 140 ms. Visual stimulation was combined with controlled hyperventilation and carbon dioxide inhalation to perform fMRI at six levels of end-expiratory pCO(2) (PETCO(2)) between 20 and 70 mm Hg. T(*)(2) in visual cortex during baseline conditions (light off) increased nonlinearly from 20 to 70 mm Hg, from 61.1 +/- 4.2 ms to 72.0 +/- 4.6 ms. Changes in T(*)(2) due to visual stimulation increased 2.1-fold, from 1.2 +/- 0.6 ms at 20 mm Hg to 2.5 +/- 0.7 ms at 50 mm Hg. An almost complete loss of functional contrast was measured at 70 mm Hg. The model of MR signal dephasing by Yablonskiy and Haacke (Mag Reson Med 1994;32:749-763) was used to predict changes in cerebral blood flow (CBF), which were found to be consistent with results from previous positron emission tomography (PET) studies. This study further emphasizes that global CBF changes (due to PETCO(2) changes even in the physiological range) strongly influence fMRI contrast and need to be controlled for.     

Source of nonlinearity in echo-time-dependent BOLD fMRI.

Stimulation-induced changes in transverse relaxation rates can provide important insight into underlying physiological changes in blood oxygenation level-dependent (BOLD) contrast. It is often assumed that BOLD fractional signal change (DeltaS/S) is linearly dependent on echo time (TE). This relationship was evaluated at 9.4 T during visual stimulation in cats with gradient-echo (GE) and spin-echo (SE) echo-planar imaging (EPI). The TE dependence of GE DeltaS/S is close to linear in both the parenchyma and large vessel area at the cortical surface for TEs of 6-20 ms. However, this dependence is nonlinear for SE studies in the TE range of 16-70 ms unless a diffusion-weighting of b = 200 s/mm(2) is applied. This behavior is not caused by inflow effects, T(2)* decay during data acquisition in SE-EPI, or extravascular spin density changes. Our results are explained by a two-compartment model in which the extravascular contribution to DeltaS/S vs. TE is linear, while the intravascular contribution can be nonlinear depending on the magnetic field strength and TE. At 9.4 T, the large-vessel IV signal can be minimized by using long TE and/or moderate diffusion weighting. Thus, stimulation-induced relaxation rate changes should be carefully determined, and their physiological meanings should be interpreted with caution.     

Spatial and temporal characteristics of physiological noise in fMRI at 3T

RATIONALE AND OBJECTIVES: Physiological noise in blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) has been shown to have characteristics similar to the BOLD signal itself, suggesting that it may have a vascular dependence. In this study, we evaluated the influence of physiological noise in fMRI as revealed by the differences in vasculature sensitivity of gradient-echo echo-planar imaging (GE-EPI) and spin-echo EPI (SE-EPI). MATERIALS AND METHODS: The contribution of physiological noise to the fMRI signal during activation of the visual cortex was assessed by comparing its temporal characteristics with respect to echo time (TE), using both GE-EPI and SE-EPI. The correlation of the noise in fMRI with apparent diffusion coefficient (ADC) and the number of components required to describe its variance, as determined by principal-component analysis (PCA), were also assessed. RESULTS: The SE-EPI data were less affected by a TE-dependence of noise, in contrast to the apparent physiological noise in GE-EPI. Voxel-wise analysis revealed that total apparent noise increased as ADC values increased, and the relationship was different for GE-EPI and SE-EPI. PCA revealed that while the number of components characterizing the noise in SE-EPI data increased in a TE-dependent manner, approaching that of white noise at long echo time, the number of components from GE-EPI data was TE-independent. CONCLUSIONS: The difference in sensitivities to physiological noise between SE-EPI and GE-EPI suggests that extravascular BOLD processes around draining veins contribute significantly to physiological noise in BOLD fMRI, and the suppression of this noise component may enhance SE-EPI BOLD sensitivity at higher fields.     

Comparison of diffusion-weighted high-resolution CBF and spin-echo BOLD fMRI at 9.4 T.

The quantification of blood oxygenation-level dependent (BOLD) functional MRI (fMRI) signals is closely related to cerebral blood flow (CBF) change; therefore, understanding the exact relationship between BOLD and CBF changes on a pixel-by-pixel basis is fundamental. In this study, quantitative CBF changes induced by neural activity were used to quantify BOLD signal changes during somatosensory stimulation in alpha-chloralose-anesthetized rats. To examine the influence of fast-moving vascular spins in quantifying CBF, bipolar gradients were employed. Our data show no significant difference in relative CBF changes obtained with and without bipolar gradients. To compare BOLD and CBF signal changes induced by neural stimulation, a spin-echo (SE) sequence with long SE time of 40 ms at 9.4 T was used in conjunction with an arterial spin labeling technique. SE BOLD changes were quantitatively correlated to CBF changes on a pixel-by-pixel and animal-by-animal basis. Thus, SE BOLD-based fMRI at high magnetic fields allows a quantitative comparison of functional brain activities across brain regions and subjects.     

Radial fast spin-echo method for T2-weighted imaging and T2 mapping of the liver

PURPOSE: To evaluate a multishot radial fast-spin echo (RAD-FSE) method developed to improve the quality of abdominal T2-weighted imaging as well as the characterization of focal liver lesions. MATERIALS AND METHODS: The RAD-FSE sequence used in this work consisted of a preparatory period followed by a short echo train (ETL = 16). A novel radial k-space trajectory was used to minimize streaking artifacts due to T2 variations and motion. Small diffusion gradients (b = 1.2 mm/s(2)) were used to improve flow suppression. The quality of images obtained with RAD-FSE was compared to multishot 2DFT fast spin-echo (2DFT-FSE) and half-Fourier acquisition single-shot turbo-spin-echo (HASTE) images using data from 16 patients. A postprocessing algorithm was used to generate multiple high-resolution images (at different effective TE values) as well as a T2 map from a single RAD-FSE data set. The T2 maps were used to differentiate malignant from benign lesions for a set of 33 lesions ranging from 0.8-194 cm(3). RESULTS: RAD-FSE produces high-resolution images of the liver in a breath-hold without the motion artifacts of 2DFT-FSE methods, and without the blurriness and loss of small lesion detectability of HASTE. The inclusion of diffusion weighting in RAD-FSE decreases the signal from blood in hepatic vessels, which improves lesion visualization. The T2 values obtained by postprocessing a single RAD-FSE data set can differentiate malignant from benign lesions. The mean T2 values obtained for malignancies, hemangiomas, and cysts are 108 +/- 30 msec, 240 +/- 14 msec, and 572 +/- 334 msec, respectively. CONCLUSION: These results indicate that RAD-FSE produces abdominal images of higher quality than 2DFT-FSE and HASTE. In addition, lesions can be characterized using T2 maps generated from a single RAD-FSE data set.     

Three-dimensional BOLD fMRI with spin-echo characteristics using T2 magnetization preparation and echo-planar readouts.

A new approach to mixed T(2)- and T(2) (*)-weighted BOLD fMRI is presented, which combines T(2) magnetization preparation (T2prep) with a series of EPI readouts. This technique allows full 3D, time-efficient imaging to be performed with low RF power deposition. Steady-state calculations are performed in order to study signal formation in 3D T2prep-EPI sequences. Results obtained under the hypothesis of ideal spoiling are compared to full Bloch equation solutions. The theoretical findings are validated by means of in vitro and in vivo signal measurements. Several variants of the 3D T2prep-EPI approach are shown to be usable for visual cortex fMRI and compared to conventional 3D coherent gradient-echo EPI. The relative sensitivity of these sequences is shown to be predictable by means of a simple DeltaT(2)/DeltaT(2) (*) model.     

Microvascular BOLD contribution at 4 and 7 T in the human brain: gradient-echo and spin-echo fMRI with suppression of blood effects.

The BOLD signal consists of an intravascular (IV) and an extravascular (EV) component from both small and large vessels. Their relative contributions are dependent on field strength, imaging technique, and echo time. The IV and EV contributions were investigated in the human visual cortex at 4 and 7 T using spin-echo and gradient-echo BOLD fMRI with and without suppression of blood effects. Spin-echo acquisition suppresses EV BOLD from large veins and reflects predominantly blood T(2) changes and EV BOLD signal from small blood vessels. At a short echo time (32 ms), diffusion gradient-based suppression of blood signals resulted in a 75% and 20% decrease in spin-echo BOLD changes at 4 T and 7 T, respectively. However, at echo times (55-65 ms) approximating tissue T(2) typically used for optimal BOLD contrast, these gradients had much smaller effects at both fields, consistent with the decreasing blood T(2) with increasing field strength. Gradient-echo BOLD percent changes, with relatively long echo times at both fields, were virtually unaffected by gradients that attenuated the blood contribution because the EV BOLD surrounding both large and small vessels dominated. These results suggest that spin-echo BOLD fMRI at 4 and 7 T, with TE approximating tissue T(2), significantly reduces nonspecific mapping signals from large vessels and significantly accentuates microvasculature contributions.     

fMRI studies of sensitivity and habituation effects within the auditory cortex at 1.5 T and 3 T

PURPOSE: To assess habituation effects in relation to field strength by fMRI at 1.5 vs. 3.0 T within the auditory cortex of healthy subjects. MATERIALS AND METHODS: fMRI experiments were performed on 19 healthy subjects at 1.5 T (N = 12) and 3 T (N = 12). The auditory cortex was stimulated binaurally by digitally generated pulsed (nu = 5 Hz) 800 Hz sine tones with three alternating on and off periods. RESULTS: The mean activation after stimulation (4.4% +/- 1.2% (1.5 T) and 5.3% +/- 2.3% (3 T)) and number of activated pixels (96.7 +/- 49.8 (1.5 T) and 139.9 +/- 101 (3 T)) were higher at 3 T compared to 1.5 T; however, that difference did not reach statistical significance. A characteristic signal decay with repeated stimuli was revealed at both 1.5 and 3 T, and the response to the second and third stimulation blocks was significantly lower compared to the first. The habituation pattern was the same, independently of field strength and age. CONCLUSION: The mean activation and number of pixels were only modestly higher at 3 T, probably due to higher physiologic noise and higher local macroscopic susceptibility gradients within the temporal lobes at 3 T. Our data reveal that measured auditory habituation is independent of field strength, and data obtained at two different field strengths do not differ fundamentally in this context.     

Full-brain coverage and high-resolution imaging capabilities of passband b-SSFP fMRI at 3T.

Passband balanced-steady-state free precession (b-SSFP) fMRI is a recently developed method that utilizes the passband (flat portion) of the b-SSFP off-resonance response to measure MR signal changes elicited by changes in tissue oxygenation following increases in neuronal activity. Rapid refocusing and short readout durations of b-SSFP, combined with the relatively large flat portion of the b-SSFP off-resonance spectrum allows distortion-free full-brain coverage with only two acquisitions. This allows for high-resolution functional imaging, without the spatial distortion frequently encountered in conventional high-resolution functional images. Finally, the 3D imaging compatibility of the b-SSFP acquisitions permits isotropic-voxel-size high-resolution acquisitions. In this study we address some of the major technical issues involved in obtaining passband b-SSFP-based functional brain images with practical imaging parameters and demonstrate the advantages through breath-holding and visual field mapping experiments.     

Single-shot T2(*) measurement to establish optimum echo time for fMRI: studies of the visual, motor, and auditory cortices at 3.0 T.

The signal change in fMRI is dependent on the echo time and the rate of decay of transverse magnetization. The latter factor may vary across regions of the brain as a result of variations in field homogeneity. Previous measurements of the signal change with echo time have generally employed relatively slow multi-echo techniques, which may be sensitive to movement and habituation effects. Here a fast T(2)(*) measurement technique, involving the generation of six low-resolution echo planar images from a single FID, is described, and its use in the evaluation of the optimum echo time for visual, motor, and auditory fMRI experiments at 3.0 T is outlined.     

Spin-echo fMRI in humans using high spatial resolutions and high magnetic fields.

The Hahn spin-echo (HSE)-based BOLD effect at high magnetic fields is expected to provide functional images that originate exclusively from the microvasculature. The blood contribution that dominates HSE BOLD contrast at low magnetic fields (e.g., 1.5 T), and degrades specificity, is highly attenuated at high fields because the apparent T(2) of venous blood in an HSE experiment decreases quadratically with increasing magnetic field. In contrast, the HSE BOLD contrast is believed to arise from the microvasculature and increase supralinearly with the magnetic field strength. In this work we report the results of detailed and quantitative evaluations of HSE BOLD signal changes for functional imaging in the human visual cortex at 4 and 7 T. This study used high spatial resolution, afforded by the increased signal-to-noise ratio (SNR) of higher field strengths and surface coils, to avoid partial volume effects (PVEs), and demonstrated increased contrast-to-noise ratio (CNR) and spatial specificity at the higher field strengths. The HSE BOLD signal changes induced by visual stimulation were predominantly linearly dependent on the echo time (TE). They increased in magnitude almost quadratically in going from 4 to 7 T when the blood contribution was suppressed using Stejskal-Tanner gradients that suppress signals from the blood due to its inhomogeneous flow and higher diffusion constant relative to tissue. The HSE signal changes at 7 T were modeled accurately using a vascular volume of 1.5%, in agreement with the capillary volume of gray matter. Furthermore, high-resolution acquisitions indicate that CNR increased with voxel sizes < 1 mm(3) due to diminishing white matter or cerebrospinal fluid-space vs. gray matter PVEs. It was concluded that the high-field HSE functional MRI (fMRI) signals originated largely from the capillaries, and that the magnitude of the signal changes associated with brain function reached sufficiently high levels at 7 T to make it a useful approach for mapping on the millimeter to submillimeter spatial scale.     

Quantifying the blood oxygenation level dependent effect in cerebral blood volume-weighted functional MRI at 9.4T.

In cerebral blood volume (CBV)-weighted functional MRI (fMRI) employing superparamagnetic contrast agent, iron dose and blood oxygenation level dependent (BOLD) contamination are two important issues for experimental design and CBV quantification. Both BOLD and CBV-weighted fMRI are based upon the susceptibility effect, to which spin-echo and gradient-echo sequences have different sensitivities. In the present study, CBV-weighted fMRI was conducted using spin-echo and gradient-echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV-weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extravascular (EV) BOLD effect. With a TE of 35 ms, the EV BOLD effect was estimated to account for 76+/-12% of the observed spin-echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation-induced CBV changes at high field.     

A qualitative test of the balloon model for BOLD-based MR signal changes at 3T.

The aim of this study was to adapt the balloon model for BOLD-based MR signal changes to a magnetic field strength of 3T and to examine its validity. The simultaneous measurement of BOLD and diffusion-weighted BOLD responses was performed. The amplitude of the BOLD peak was found to be similar for all subjects when a short visual stimulus of 6 sec was used. The rise-time to the BOLD peak and the shape and depth of the poststimulus undershoot varied significantly. A fit of the experimental BOLD responses was found to be possible by use of parameters within a reasonable physiological range. The relations between these parameters and their influence on the modeled BOLD responses is discussed. A prediction of the balloon model is the occurrence of a BOLD overshoot, i.e., a lag between the changes of the blood volume and the blood flow after the start of the stimulation. Experimental evidence for the existence of a BOLD overshoot is presented.     

Is there a change in water proton density associated with functional magnetic resonance imaging?

In a recent series of studies (see, for example, Stroman et al. Magn Reson Imag 2001; 19:827-831), an increase of water proton density has been suggested to correlate with neuronal activity. Owing to the significant implications of such a mechanism for other functional experiments, the functional signal changes in humans at very short echo times were re-examined by spin-echo EPI at 3 T. The results do not confirm the previous hypothesis of a significant increase in extravascular proton density at TE = 0. Instead, an alternative explanation of the effect is offered: The use of a low threshold to identify activated voxels may generate an artificial offset in functional contrast due to the inclusion of false-positives in the analysis.     

Multishot partial-k-space EPI for high-resolution fMRI demonstrated in a rat whisker barrel stimulation model at 3T.

A multishot partial-k-space EPI technique is presented and validated by fMRI at high spatial resolution. High-resolution phase maps corrected by phase-encoded reference scans have less off-resonance effects. Phantom studies demonstrate that this method can substantially improve partial-k-space EPI image formation. BOLD fMRI at submillimeter spatial resolution (156 x 156 x 2000 microm(3), 0.049 microl) was achieved in a rat whisker barrel stimulation model using this technique. The study included eight rats, five of which were administered an intravascular contrast agent (monocrystalline iron oxide nanocolloid (MION)) after the BOLD experiments. In two rats the highest BOLD responses were in the deep layers (IV-VI), and in six rats the highest responses were on the surface and in the deep cortical layers. Most of the pixels that exhibited high BOLD responses had high blood volume weightings. The benefits of this technique are expected to increase for high-resolution fMRI at higher magnetic fields, where T(2) (*) is shorter.     

Quantifying hemodynamic refractory bold effects in normal subjects at the single-subject level using an inverse logit fitting procedure

Purpose:

To evaluate whether hemodynamic refractory effects provoked by repeated visual stimulation can be detected and quantified at the single‐subject level using a recently described hemodynamic response function (HRF) fitting algorithm.

Materials and Methods:

Hemodynamic refractory effects were induced with an easily applicable functional MRI (fMRI) paradigm. A fitting method with inverse logit (IL) functions was applied to quantify net HRFs at the single‐subject level with three interstimulus intervals (ISI; 1, 2, and 6 s). The model yielded amplitude, latencies, and width for each HRF.

Results:

HRF fitting was possible in 44 of 51 healthy volunteers, with excellent goodness‐of‐fit (R² = 0.9745 ± 0.0241). Refractory effects were most pronounced for the 1‐s ISI (P < 0.001) and had nearly disappeared for the 6‐s ISI.

Conclusion:

Quantifying refractory effects in individuals was possible in 86.3% of normal subjects using the IL fitting algorithm. This setup may be suitable to explore such effects in individual patients. J. Magn. Reson. Imaging 2012;35:723‐730. © 2011 Wiley Periodicals, Inc.