Craig K. Jones

MRI detection of glycogen in vivo by using chemical exchange saturation transfer imaging (glycoCEST).

Detection of glycogen in vivo would have utility in the study of normal physiology and many disorders. Presently, the only magnetic resonance (MR) method available to study glycogen metabolism in vivo is 13C MR spectroscopy, but this technology is not routinely available on standard clinical scanners. Here, we show that glycogen can be detected indirectly through the water signal by using selective radio frequency (RF) saturation of the hydroxyl protons in the 0.5- to 1.5-ppm frequency range downfield from water. The resulting saturated spins are rapidly transferred to water protons via chemical exchange, leading to partial saturation of the water signal, a process now known as chemical exchange saturation transfer. This effect is demonstrated in glycogen phantoms at magnetic field strengths of 4.7 and 9.4 T, showing improved detection at higher field in adherence with MR exchange theory. Difference images obtained during RF irradiation at 1.0 ppm upfield and downfield of the water signal showed that glycogen metabolism could be followed in isolated, perfused mouse livers at 4.7 T before and after administration of glucagon. Glycogen breakdown was confirmed by measuring effluent glucose and, in separate experiments, by 13C NMR spectroscopy. This approach opens the way to image the distribution of tissue glycogen in vivo and to monitor its metabolism rapidly and noninvasively with MRI.

Effects of signal‐to‐noise ratio on the accuracy and reproducibility of diffusion tensor imaging–derived fractional anisotropy, mean diffusivity, and principal eigenvector measurements at 1.5T

To develop an experimental protocol to calculate the precision and accuracy of fractional anisotropy (FA), mean diffusivity (MD), and the orientation of the principal eigenvector (PEV) as a function of the signal‐to‐noise ratio (SNR) in vivo.

Effects of diffusion weighting schemes on the reproducibility of DTI-derived fractional anisotropy, mean diffusivity, and principal eigenvector measurements at 1.5T

Diffusion tensor imaging (DTI) is used to study tissue composition and architecture in vivo. To increase the signal to noise ratio (SNR) of DTI contrasts, studies typically use more than the minimum of 6 diffusion weighting (DW) directions or acquire repeated observations of the same set of DW directions. Simulation-based studies have sought to optimize DTI acquisitions and suggest that increasing the directional resolution of a DTI dataset (i.e., the number of distinct directions) is preferable to repeating observations, in an equal scan time comparison. However, it is not always clear how to translate these recommendations into practice when considering physiological noise and scanner stability. Furthermore, the effect of different DW schemes on in vivo DTI findings is not fully understood. This study characterizes how the makeup of a DW scheme, in terms of the number of directions, impacts the precision and accuracy of in vivo fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) findings. Orientation dependence of DTI reliability is demonstrated in vivo and a principled theoretical framework is provided to support and interpret findings with simulation results. As long as sampling orientations are well balanced, differences in DTI contrasts due to different DW schemes are shown to be small relative to intra-session variability. These differences are accentuated at low SNR, while minimized at high SNR. This result suggests that typical clinical studies, which use similar protocols but different well-balanced DW schemes, are readily comparable within the experimental precision.

Amide proton transfer imaging of human brain tumors at 3T

Amide proton transfer (APT) imaging is a technique in which the nuclear magnetization of water‐exchangeable amide protons of endogenous mobile proteins and peptides in tissue is saturated, resulting in a signal intensity decrease of the free water. In this work, the first human APT data were acquired from 10 patients with brain tumors on a 3T whole‐body clinical scanner and compared with T1‐ (T1w) and T2‐weighted (T2w), fluid‐attenuated inversion recovery (FLAIR), and diffusion images (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)). The APT‐weighted images provided good contrast between tumor and edema. The effect of APT was enhanced by an approximate 4% change in the water signal intensity in tumor regions compared to edema and normal‐appearing white matter (NAWM). These preliminary data from patients with brain tumors show that the APT is a unique contrast that can provide complementary information to standard clinical MRI measures. Magn Reson Med, 2006.

Quantitative Description of the Asymmetry in Magnetization Transfer Effects around the Water Resonance in the Human Brain

Magnetization transfer (MT) imaging provides a unique method of tissue characterization by capitalizing on the interaction between solid‐like tissue components and bulk water. We used a continuous‐wave (CW) MT pulse sequence with low irradiation power to study healthy human brains in vivo at 3 T and quantified the asymmetry of the MT effects with respect to the water proton frequency. This asymmetry was found to be a difference of approximately a few percent from the water signal intensity, depending on both the RF irradiation power and the frequency offset. The experimental results could be quantitatively described by a modified two‐pool MT model extended with a shift contribution for the semisolid pool with respect to water. For white matter, this shift was fitted to be 2.34 ± 0.17 ppm (N = 5) upfield from the water signal. Magn Reson Med 58:786–793, 2007.

Nuclear Overhauser Enhancement (NOE) Imaging in the Human Brain at 7 T

Chemical exchange saturation transfer (CEST) is a magnetization transfer (MT) technique to indirectly detect pools of exchangeable protons through the water signal. CEST MRI has focused predominantly on signals from exchangeable protons downfield (higher frequency) from water in the CEST spectrum. Low power radiofrequency (RF) pulses can slowly saturate protons with minimal interference of conventional semi-solid based MT contrast (MTC). When doing so, saturation-transfer signals are revealed upfield from water, which is the frequency range of non-exchangeable aliphatic and olefinic protons. The visibility of such signals indicates the presence of a relayed transfer mechanism to the water signal, while their finite width reflects that these signals are likely due to mobile solutes. It is shown here in protein phantoms and the human brain that these signals build up slower than conventional CEST, at a rate typical for intramolecular nuclear Overhauser enhancement (NOE) effects in mobile macromolecules such as proteins/peptides and lipids. These NOE-based saturation transfer signals show a pH dependence, suggesting that this process is the inverse of the well-known exchange-relayed NOEs in high resolution NMR protein studies, thus a relayed-NOE CEST process. When studying 6 normal volunteers with a low-power pulsed CEST approach, the relayed-NOE CEST effect was about twice as large as the CEST effects downfield and larger in white matter than gray matter. This NOE contrast upfield from water provides a way to study mobile macromolecules in tissue. First data on a tumor patient show reduction in both relayed NOE and CEST amide proton signals leading to an increase in magnetization transfer ratio asymmetry, providing insight into previously reported amide proton transfer (APT) effects in tumors.

In vivo three-dimensional whole-brain pulsed steady-state chemical exchange saturation transfer at 7 T

Chemical exchange saturation transfer (CEST) is a technique to indirectly detect pools of exchangeable protons through the water signal. To increase its applicability to human studies, it is needed to develop sensitive pulse sequences for rapidly acquiring whole‐organ images while adhering to stringent amplifier duty cycle limitations and specific absorption rate restrictions. In addition, the interfering effects of direct water saturation and conventional magnetization transfer contrast complicate CEST quantification and need to be reduced as much as possible. It is shown that for protons exchanging with rates of less than 50–100 Hz, such as imaged in amide proton transfer experiments, these problems can be addressed by using a three‐dimensional steady state pulsed acquisition of limited B1 strength (∼1 μT). Such an approach exploits the fact that the direct water saturation width, magnetization transfer contrast magnitude, and specific absorption rate increase strongly with B1, while the size of the CEST effect for such protons depends minimally on B1. A short repetition time (65 ms) steady‐state sequence consisting of a brief saturation pulse (25 ms) and a segmented echo‐planar imaging train allowed acquisition of a three‐dimensional whole‐brain volume in approximately 11 s per saturation frequency, while remaining well within specific absorption rate and duty cycle limits. Magnetization transfer contrast was strongly reduced, but substantial saturation effects were found at frequencies upfield from water, which still confound the use of magnetization transfer asymmetry analysis. Fortunately, the limited width of the direct water saturation signal could be exploited to fit it with a Lorentzian function allowing CEST quantification. Amide proton transfer effects ranged between 1.5% and 2.5% in selected white and grey matter regions. This power and time‐efficient 3D pulsed CEST acquisition scheme should aid endogenous CEST quantification at both high and low fields. Magn Reson Med, 2011.

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 × 1.89 × 3 mm3), 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 (≤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. Magn Reson Med, 2006.

High-resolution fMRI investigation of the medial temporal lobe

The medial temporal lobe (MTL) is critical for declarative memory formation. Several theories of MTL function propose functional distinctions between the different structures of the MTL, namely the hippocampus and the surrounding cortical areas. Furthermore, computational models and electrophysiological studies in animals suggest distinctions between the subregions of the hippocampus itself. Standard fMRI resolution is not sufficiently fine to resolve activity on the scale of hippocampal subregions. Several approaches to scanning the MTL at high resolutions have been made, however there are limitations to these approaches, namely difficulty in conducting group‐level analyses. We demonstrate here techniques for scanning the MTL at high resolution and analyzing the high‐resolution fMRI data at the group level. To address the issue of cross‐participant alignment, we employ the ROI‐LDDMM alignment technique, which is demonstrated to result in smaller alignment errors when compared with several other common normalization techniques. Finally, we demonstrate that the pattern of activation obtained in the high‐resolution functional data is similar to that obtained at lower resolution, although the spatial extent is smaller and the percent signal change is greater. This difference in the pattern of activation may be due to less partial volume sampling in the high‐resolution data, resulting in more accentuated regions of activation. Hum Brain Mapp 2006.

Applications of stimulated echo correction to multicomponent T2 analysis

We propose a multicomponent fitting algorithm for multiecho T2 data which allows for correction of T2 distributions in the presence of stimulated echoes. Tracking the population of spins in many coherence pathways via the iterated method of the Extended Phase Graph algorithm allows for accurate quantification of echo magnitudes. The resulting decay curves allow for correction of errors due to nonideal refocusing pulses as a result of inhomogeneities in the B1 transmit field. Non‐Negative Least Squares fitting is used to quantify the magnitude of T2 components at various T2 values. This method, allowing calculation of the T2 distribution with simultaneous extraction of the refocusing pulse flip angle, requires no change to image acquisition procedures and no extra data input. Validation by means of both simulations and in vivo data shows excellent interscan reproducibility while vastly improving the accuracy of extracted T2 parameters in voxels where poor B1 homogeneity leads to refocusing pulse flip angles significantly less than 180°. Most notably, myelin water fraction values in these regions are found to have increased consistency and accuracy. Magn Reson Med, 2011.