Peter C.M. van Zijl

Reproducibility of Quantitative Tractography Methods Applied to Cerebral White Matter

Tractography based on diffusion tensor imaging (DTI) allows visualization of white matter tracts. In this study, protocols to reconstruct eleven major white matter tracts are described. The protocols were refined by several iterations of intra- and inter-rater measurements and identification of sources of variability. Reproducibility of the established protocols was then tested by raters who did not have previous experience in tractography. The protocols were applied to a DTI database of adult normal subjects to study size, fractional anisotropy (FA), and T2 of individual white matter tracts. Distinctive features in FA and T2 were found for the corticospinal tract and callosal fibers. Hemispheric asymmetry was observed for the size of white matter tracts projecting to the temporal lobe. This protocol provides guidelines for reproducible DTI-based tract-specific quantification.

DtiStudio: Resource program for diffusion tensor computation and fiber bundle tracking

A versatile resource program was developed for diffusion tensor image (DTI) computation and fiber tracking. The software can read data formats from a variety of MR scanners. Tensor calculation is performed by solving an over-determined linear equation system using least square fitting. Various types of map data, such as tensor elements, eigenvalues, eigenvectors, diffusion anisotropy, diffusion constants, and color-coded orientations can be calculated. The results are visualized interactively in orthogonal views and in three-dimensional mode. Three-dimensional tract reconstruction is based on the Fiber Assignment by Continuous Tracking (FACT) algorithm and a brute-force reconstruction approach. To improve the time and memory efficiency, a rapid algorithm to perform the FACT is adopted. An index matrix for the fiber data is introduced to facilitate various types of fiber bundles selection based on approaches employing multiple regions of interest (ROIs). The program is developed using C++ and OpenGL on a Windows platform.

Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI

In the past decade, it has become possible to use the nuclear (proton, 1H) signal of the hydrogen atoms in water for noninvasive assessment of functional and physiological parameters with magnetic resonance imaging (MRI). Here we show that it is possible to produce pH-sensitive MRI contrast by exploiting the exchange between the hydrogen atoms of water and the amide hydrogen atoms of endogenous mobile cellular proteins and peptides. Although amide proton concentrations are in the millimolar range, we achieved a detection sensitivity of several percent on the water signal (molar concentration). The pH dependence of the signal was calibrated in situ, using phosphorus spectroscopy to determine pH, and proton exchange spectroscopy to measure the amide proton transfer rate. To show the potential of amide proton transfer (APT) contrast for detecting acute stroke, pH effects were noninvasively imaged in ischemic rat brain. This observation opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, as diagnostic tools in clinical imaging.

Imaging cortical association tracts in the human brain using diffusion‐tensor‐based axonal tracking

Diffusion‐tensor fiber tracking was used to identify the cores of several long‐association fibers, including the anterior (ATR) and posterior (PTR) thalamic radiations, and the uncinate (UNC), superior longitudinal (SLF), inferior longitudinal (ILF), and inferior fronto‐occipital (IFO) fasciculi. Tracking results were compared to existing anatomical knowledge, and showed good qualitative agreement. Guidelines were developed to reproducibly track these fibers in vivo. The interindividual variability of these reconstructions was assessed in a common spatial reference frame (Talairach space) using probabilistic mapping. As a first illustration of this technical capability, a reduction in brain connectivity in a patient with a childhood neurodegenerative disease (X‐linked adrenoleukodystrophy) was demonstrated. Magn Reson Med 47:215–223, 2002.

Determining the longitudinal relaxation time (T1) of blood at 3.0 Tesla.

It is important to determine the longitudinal relaxation time of blood for black blood imaging, as well as for quantifying blood flow by arterial spin labeling (ASL). In this study a circulation system was used to measure blood T1 under physiological conditions at the new clinical field strength of 3.0T. It was found that 1/T1 in s−1 was linearly dependent (P < 0.05) on hematocrit (Hct) within a normal range of 0.38–0.46. The relationships were 1/T1 = (0.52 ± 0.15) · Hct + (0.38 ± 0.06) and 1/T1 = (0.83 ± 0.07) · Hct + (0.28 ± 0.03) for arterial (oxygenation = 92% ± 7%) and venous blood (69% ± 8%), respectively, which led to estimated T1 values of 1664 ± 14 ms (arterial) and 1584 ± 5 ms (venous) at a typical human Hct of 0.42. The temperature dependencies of blood T1 were 22.3 ± 0.6 ms/°C and 19.8 ± 0.8 ms/°C for Hct values of 0.42 and 0.38, respectively. When a head coil transmit/receive setup was used, radiation damping caused a slight reduction (19 ms) of the measured T1 values. Magn Reson Med 52:679–682, 2004.

Diffusion tensor imaging and axonal tracking in the human brainstem.

Diffusion tensor MRI was used to demonstrate in vivo anatomical mapping of brainstem axonal connections. It was possible to identify the corticospinal tract (CST), medial lemniscus, and the superior, medial, and inferior cerebellar peduncles. In addition, the cerebral peduncle could be subparcellated into component tracts, namely, the frontopontine tract, the CST, and the temporo-/parieto-/occipitopontine tract. Anatomical landmarks and tracking thresholds were established for each fiber and, using these standards, reproducibility of automated tracking as assessed by intra- and interrater reliability was found to be high (kappa > 0.82). Reconstructed fibers corresponded well to existing anatomical knowledge, validating the tracking. Information on the location of individual tracts was coregistered with quantitative MRI maps to automatically measure MRI parameters on a tract-by-tract basis. The results reveal that each tract has a unique spatial signature in terms of water relaxation and diffusion anisotropy.

Chemical exchange saturation transfer (CEST): What is in a name and what isn't?

Chemical exchange saturation transfer (CEST) imaging is a relatively new magnetic resonance imaging contrast approach in which exogenous or endogenous compounds containing either exchangeable protons or exchangeable molecules are selectively saturated and after transfer of this saturation, detected indirectly through the water signal with enhanced sensitivity. The focus of this review is on basic magnetic resonance principles underlying CEST and similarities to and differences with conventional magnetization transfer contrast. In CEST magnetic resonance imaging, transfer of magnetization is studied in mobile compounds instead of semisolids. Similar to magnetization transfer contrast, CEST has contributions of both chemical exchange and dipolar cross‐relaxation, but the latter can often be neglected if exchange is fast. Contrary to magnetization transfer contrast, CEST imaging requires sufficiently slow exchange on the magnetic resonance time scale to allow selective irradiation of the protons of interest. As a consequence, magnetic labeling is not limited to radio‐frequency saturation but can be expanded with slower frequency‐selective approaches such as inversion, gradient dephasing and frequency labeling. The basic theory, design criteria, and experimental issues for exchange transfer imaging are discussed. A new classification for CEST agents based on exchange type is proposed. The potential of this young field is discussed, especially with respect to in vivo application and translation to humans. Magn Reson Med, 2011.

Amide proton transfer (APT) contrast for imaging of brain tumors

In this work we demonstrate that specific MR image contrast can be produced in the water signal that reflects endogenous cellular protein and peptide content in intracranial rat 9L gliosarcomas. Although the concentration of these mobile proteins and peptides is only in the millimolar range, a detection sensitivity of several percent on the water signal (molar concentration) was achieved. This was accomplished with detection sensitivity enhancement by selective radiofrequency (RF) labeling of the amide protons, and by utilizing the effective transfer of this label to water via hydrogen exchange. Brain tumors were also assessed by conventional T1‐weighted, T2‐weighted, and diffusion‐weighted imaging. Whereas these commonly‐used approaches yielded heterogeneous images, the new amide proton transfer (APT) technique showed a single well‐defined region of hyperintensity that was assigned to brain tumor tissue. Magn Reson Med 50:1120–1126, 2003.

Pediatric diffusion tensor imaging: Normal database and observation of the white matter maturation in early childhood

Recent advances in diffusion tensor imaging (DTI) have made it possible to reveal white matter anatomy and to detect neurological abnormalities in children. However, the clinical use of this technique is hampered by the lack of a normal standard of reference. The goal of this study was to initiate the establishment of a database of DTI images in children, which can be used as a normal standard of reference for diagnosis of pediatric neurological abnormalities. Seven pediatric volunteers and 23 pediatric patients (age range: 0-54 months) referred for clinical MR examinations, but whose brains were shown to be normal, underwent anatomical and DTI acquisitions on a 1.5 T MR scanner. The white matter maturation, as observed on DTI color maps, was described and illustrated. Changes in diffusion fractional anisotropy (FA), average apparent diffusion constant (ADC(ave)), and T2-weighted (T2W) signal intensity were quantified in 12 locations to characterize the anatomical variability of the maturation process. Almost all prominent white matter tracts could be identified from birth, although their anisotropy was often low. The evolution of FA, shape, and size of the white matter tracts comprised generally three phases: rapid changes during the first 12 months; slow modifications during the second year; and relative stability after 24 months. The time courses of FA, ADC(ave), and T2W signal intensity confirmed our visual observations that maturation of the white matter and the normality of its architecture can be assessed with DTI in young children. The database is available online and is expected to foster the use of this promising technique in the diagnosis of pediatric pathologies.

Artificial reporter gene providing MRI contrast based on proton exchange

Existing magnetic resonance reporter genes all rely on the presence of (super)paramagnetic substances and employ water relaxation to gain contrast. We designed a nonmetallic, biodegradable, lysine rich–protein (LRP) reporter, the prototype of a potential family of genetically engineered reporters expressing artificial proteins with frequency-selective contrast. This endogenous contrast, based on transfer of radiofrequency labeling from the reporters amide protons to water protons, can be switched on and off.