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.     

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.     

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.     

Quantifying the intra- and extravascular contributions to spin-echo fMRI at 3 T.

Functional MRI (fMRI) by means of spin-echo (SE) techniques provides an interesting alternative to gradient-echo methods because the contrast is based primarily on dynamic averaging associated with the blood oxygenation level-dependent (BOLD) effect. In this article the contributions from different brain compartments to BOLD signal changes in SE echo planar imaging (EPI) are investigated. To gain a better understanding of the underlying mechanisms that cause the fMRI contrast, two experiments are presented: First, the intravascular contribution is decomposed into two fractions with different regimes of flow by means of diffusion-weighting gradient schemes which are either flow-compensated, or will maximally dephase moving spins. Second, contributions from the intra- and extravascular space are selectively suppressed by combining flow-weighting with additional refocusing pulses. The results indicate two qualitatively different components of flowing blood which contribute to the BOLD contrast and a nearly equal share in functional signal from the intra- and extravascular compartments at TE approximately 80 ms and 3 T. Combining these results, there is evidence that at least one-half of the functional signal originates from the parenchyma in SE fMRI at 3 T. The authors suggest the use of flow-compensated diffusion weighting for SE fMRI to improve the sensitivity to the parenchyma.     

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.     

Imaging brain function in humans at 7 Tesla.

This article describes experimental studies performed to demonstrate the feasibility of BOLD fMRI using echo-planar imaging (EPI) at 7 T and to characterize the BOLD response in humans at this ultrahigh magnetic field. Visual stimulation studies were performed in normal subjects using high-resolution multishot EPI sequences. Changes in R(*)(2) arising from visual stimulation were experimentally determined using fMRI measurements obtained at multiple echo times. The results obtained at 7 T were compared to those at 4 T. Experimental data indicate that fMRI can be reliably performed at 7 T and that at this field strength both the sensitivity and spatial specificity of the BOLD response are increased. This study suggests that ultrahigh field MR systems are advantageous for functional mapping in humans. Magn Reson Med 45:588-594, 2001.     

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.     

High-resolution fMRI using multislice partial k-space GR-EPI with cubic voxels.

The premises of this work are: 1) the limit of spatial resolution in fMRI is determined by anatomy of the microcirculation; 2) because of cortical gray matter tortuosity, fMRI experiments should (in principle) be carried out using cubic voxels; and 3) the noise in fMRI experiments is dominated by low-frequency BOLD fluctuations that are a consequence of spontaneous neuronal events and are pixel-wise dependent. A new model is proposed for fMRI contrast which predicts that the contrast-to-noise ratio (CNR) tends to be independent of voxel dimensions (in the absence of partial voluming of activated tissue), TE, and scanner bandwidth. These predictions have been tested at 3 T, and results support the model. Scatter plots of fMRI signal intensities and low-frequency fluctuations for activated pixels in a finger-tapping paradigm demonstrated a linear relationship between signal and noise that was independent of TE. The R(2) value was about 0.9 across eight subjects studied. The CNR tended to be constant across pixels within a subject but varied across subjects: CNR = 3.2 +/- 1.0. fMRI statistics at 20- and 40-ms TE values were indistinguishable, and TE values as short as 10 ms were used successfully. Robust fMRI data were obtained across all subjects using 1 x 1 x 1 mm(3) cubic voxels with 10 contiguous slices, although 1.5 x 1.5 x 1.5 mm(3) was found to be optimum. Magn Reson Med 46:114-125, 2001.     

Cortical depth-dependent gradient-echo and spin-echo BOLD fMRI at 9.4T.

To examine cortical depth-related spatial specificity and signal changes in gradient-echo (GE) and spin-echo (SE) blood oxygenation level-dependent (BOLD) fMRI signals, a well-established cat visual stimulation model was used at 9.4T. The GE BOLD signal percent change is the highest at the surface of the cortex containing pial vessels, and decreases as cortical depth increases. In contrast, the SE BOLD signal is more specific to parenchyma, showing the highest signal change in the middle cortical areas. The stimulation-induced DeltaR2* to DeltaR2 ratio is dependent on the vessel size, which is related to basal susceptibility effects. The averaged ratio of DeltaR2* to DeltaR2 in all active regions, including large vessels, is 3.3 +/- 0.5 (N = 6). The averaged ratio of DeltaR2* to DeltaR2 is 8.8 +/- 1.7 (N = 4) on the surface of the cortex with large pial draining vessels, and decreases to 1.9 +/- 0.1 on the middle cortical areas with parenchymal microvessels. DeltaR2*/DeltaR2 is closely related to basal susceptibility effects and can be used to differentiate tissue from vessel regions.     

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.     

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.     

Sensitivity comparison of multiple vs. single inversion time pulsed arterial spin labeling fMRI

PURPOSE: To study the sensitivity for detection of activation for multiple vs. single inversion time (TI) pulsed arterial spin labeling (PASL). MATERIALS AND METHODS: The number of activated voxels and the mean t-statistic over activated voxels was measured by means of multiple and single TI PASL sequences in five volunteers during visual stimulation by means of an alternating checkerboard. Acquisition was performed by means of the transfer insensitive labeling technique (TILT) and TURBO-TILT. RESULTS: It was found that the sensitivity for the detection of activation was lower for an individual TI out of a multiple TI sequence than for the corresponding single TI acquisition of equal duration. After averaging over all TIs between and including 600 and 1400 msec, the number of activated voxels and mean t-statistic were no longer statistically lower for the multiple TI sequence than for the single TI experiment. CONCLUSION: Multiple TI PASL can be used for functional MRI (fMRI) studies, when performing the detection of activated brain regions on data that is averaged over all TIs between 600 and 1400 msec. Subsequently the multi-TI data can be used to quantify cerebral blood flow (CBF) changes upon activation. Additionally, we have shown that single TI PASL fMRI overestimates the CBF changes upon activation due to transit time changes.     

Combining spatial and temporal information to explore function‐guide action of acupuncture using fMRI

Purpose

To investigate the brain response patterns of modulation of GB37 (Guangming) and KI8 (Jiaoxin).

Materials and Methods

An experiment using nonrepeated event‐related fMRI design was carried out on 28 subjects with electroacupuncture stimulation (EAS) at GB37 or KI8 on the left leg. The discrete cosine transform and functional connectivity methods were adopted to detect the differences related with these two acupoints before and after the EAS.

Results

Spatial patterns were distinct for EAS at the two acupoints, and the overlapping brain regions were mainly located in the posterior cingulate cortex (PCC) and precuneus (pC). Two opposite patterns of modulation in the default mode network were detected from the temporal patterns with the overlapping PCC/pC as the region of interest. Furthermore, the specific responses of sustained effects at these acupoints were also identified.

Conclusion

Spatial and temporal patterns of the sustained effect modulation of GB37 and KI8 were distinct. We suggest these findings may attribute to the functional specificity of a certain acupoint. Moreover, our current results reflect a significant methodological contribution to future acupuncture studies. J. Magn. Reson. Imaging 2009;30:41–46. © 2009 Wiley‐Liss, Inc.     

BOLD imaging in the mouse brain using a turboCRAZED sequence at high magnetic fields

Functional MRI (fMRI) based on the detection of intermolecular double‐quantum coherences (iDQC) has previously been shown to provide pronounced activation signal. For fMRI in small animals at very high magnetic fields, the essential fast gradient echo‐based readout methods become problematic. Here, rapid intermolecular double‐quantum coherence (iDQC) imaging was implemented, combining the iDQC preparation sequence with a Turbo spin echo‐like readout. Four‐step phase cycling and a novel intensity‐ordered k‐space encoding scheme with separate acquisition of odd and even echoes were essential to optimize signal to noise ratio efficiency. Compared with a single echo readout of iDQC signal, acceleration of factor 16 was achieved in phantoms using the novel method at 17.6 Tesla. In vivo, echo trains consisting of 32 echoes were possible and images of the mouse brain were obtained in 30 s. The blood oxygen level dependent (BOLD) effect in the mouse brain upon change of breathing gas was observed as average signal change of (6.3 ± 1.1)% in iDQC images. Signal changes in conventional multi spin echo images were (4.4 ± 2.3)% and (8.3 ± 3.8)% with gradient echo methods. Combination of T₂*‐weighting with the fast iDQC sequence may yield higher signal changes than with either method alone, and establish fast iDQC imaging a robust tool for high field fMRI in small animals. Magn Reson Med 60:850–859, 2008. © 2008 Wiley‐Liss, Inc.     

Bayesian technique for investigating linearity in event-related BOLD fMRI.

Event-related BOLD fMRI data is modeled as a linear time-invariant system. Together with Bayesian inference techniques, a statistical test is developed for rigorously detecting linearity/nonlinearity in the BOLD response system. The test is applied to data collected from eight subjects using an event-related paradigm with a switching checkerboard as the visual stimulus. Analyzed as a group, the results clearly find the response to be nonlinear. When each subject is analyzed individually, however, the results are predominantly nonlinear, but there is some evidence to suggest that there may be a crossover from a linear to a nonlinear regime and vice versa. This could be important when estimating physiological parameters for individuals. Additionally, estimates of the hemodynamic response function and corresponding response were obtained, but there was no consistent appearance of a poststimulus undershoot in the event-related BOLD response.     

Echo-planar BOLD fMRI of mice on a narrow-bore 9.4 T magnet.

The feasibility of BOLD fMRI in association with electrical somatosensory stimulation on spontaneously breathing, isoflurane-anesthetized mice was investigated using spin-echo, echo-planar imaging (EPI) on a vertical narrow-bore 9.4 T magnet. Three experiments were performed to derive an optimal fMRI protocol. In Experiment 1 (n = 9), spin-echo BOLD responses to 10% CO2 challenge under graded isoflurane (0.25-1.25%) ranged from 10 +/- 2% to 3.5 +/- 0.9%; the optimal BOLD contrast-to-noise ratio peaked at 0.75% isoflurane. In Experiment 2 (n = 6), hindpaw somatosensory stimulations using 1-7 mA under 0.75% isoflurane revealed the optimal BOLD response was at 6 mA. In Experiment 3 (n = 5), BOLD responses to 4 and 6 mA stimulation under 0.75% and 1% isoflurane were evaluated in detail, confirming the optimal conditions in Experiment 2. These results demonstrated that BOLD fMRI using single-shot, spin-echo EPI in a mouse somatosensory stimulation model could be routinely performed on high-field, vertical, narrow-bore magnets. This protocol might prove useful for fMRI studies of transgenic mice.     

Cerebral venous and arterial blood volumes can be estimated separately in humans using magnetic resonance imaging.

Approaches to obtain quantitative, noninvasive estimates of total cerebral blood volume (tCBV) and cerebral venous blood volume (vCBV) separately in humans are proposed. Two sequences were utilized, including a 3D high-resolution gradient-echo (GE) sequence and a 2D multi-echo GE/spin-echo (MEGESE) sequence. Images acquired by the former sequence provided an estimate of background magnetic field variations (DeltaB), while images obtained by the latter sequence were utilized to obtain separate measures of tCBV and vCBV with and without contrast agent. Prior to the calculation of vCBV and tCBV, the acquired images were corrected for signal loss induced by the presence of DeltaB. vCBV and tCBV were estimated to be 2.46% +/- 0.28% and 3.20% +/- 0.41%, respectively, after the DeltaB correction, which in turn provided a vCBV/tCBV ratio of 0.77 +/- 0.04, in excellent agreement with results reported in the literature. Our results demonstrate that quantitative estimates of vCBV and tCBV can be obtained in vivo.     

Rapid full-brain fMRI with an accelerated multi shot 3D EPI sequence using both UNFOLD and GRAPPA

The desire to understand complex mental processes using functional MRI drives development of imaging techniques that scan the whole human brain at a high spatial and temporal resolution. In this work, an accelerated multishot three-dimensional echo-planar imaging sequence is proposed to increase the temporal resolution of these studies. A combination of two modern acceleration techniques, UNFOLD and GRAPPA is used in the secondary phase encoding direction to reduce the scan time effectively. The sequence (repetition time of 1.02 s) was compared with standard two-dimensional echo-planar imaging (3 s) and multishot three-dimensional echo-planar imaging (3 s) sequences with both block design and event-related functional MRI paradigms. With the same experimental setup and imaging time, the temporal resolution improvement with our sequence yields similar activation regions in the block design functional MRI paradigm with slightly increased t-scores. Moreover, additional information on the timing of rapid dynamic changes was extracted from accelerated images for the case of the event related complex mental paradigm.