This paper introduces a multi-compartment model for microscopic diffusion anisotropy imaging. The aim is to estimate microscopic features specific to the intra- and extra-neurite compartments in nervous tissue unconfounded by the effects of fibre crossings and orientation dispersion, which are ubiquitous in the brain. The proposed MRI method is based on the Spherical Mean Technique (SMT), which factors out the neurite orientation distribution and thus provides direct estimates of the microscopic tissue structure. This technique can be immediately used in the clinic for the assessment of various neurological conditions, as it requires only a widely available off-the-shelf sequence with two b-shells and high-angular gradient resolution achievable within clinically feasible scan times. To demonstrate the developed method, we use high-quality diffusion data acquired with a bespoke scanner system from the Human Connectome Project. This study establishes the normative values of the new biomarkers for a large cohort of healthy young adults, which may then support clinical diagnostics in patients. Moreover, we show that the microscopic diffusion indices offer direct sensitivity to pathological tissue alterations, exemplified in a preclinical animal model of Tuberous Sclerosis Complex (TSC), a genetic multi-organ disorder which impacts brain microstructure and hence may lead to neurological manifestations such as autism, epilepsy and developmental delay.

Oscillating gradients were used to probe the diffusion-time/ frequency dependence of water diffusion in the gray matter of normal and globally ischemic rat brain. In terms of a conventional definition of diffusion time, the oscillating gradient measurements provided the apparent diffusion coefficient (ADC) of water with diffusion times between 9.75 ms and 375 s, an order of magnitude shorter than previously studied in vivo. Over this range, ADCs increased as much as 24% in vivo and 50% postmortem, depending on the nature of the oscillating gradient waveform used. Novel waveforms were employed to sample narrow frequency bands of the so-called diffusion spectrum. This spectral description of ADC includes the effects of restriction and/or flow, and is independent of experimental parameters, such as diffusion time. The results in rat brain were found to be consistent with restricted diffusion and the known microanatomy of gray matter. Differences between normal and postmortem data were consistent with an increase in water restriction and/or a decrease in flow, and tentatively suggest that physical changes following the onset of ischemia occur on a scale of about 2 m, similar to a typical cellular dimension in gray matter. Magn Reson Med 49:206 -215, 2003. © 2003 Wiley-Liss, Inc. Key words: MRI; diffusion; restriction; ischemia; oscillating gradientWhen the Brownian motion of a molecule is physically impeded or hindered, its effective rate of self-diffusion, or apparent diffusion coefficient (ADC), is reduced, and the diffusion is said to be restricted. In tissues, restriction is thought to be a significant mechanism affecting contrast in diffusion-weighted imaging, in both normal and pathological states. In particular, restriction of water by cell membranes is believed to be the dominant mechanism causing diffusion anisotropy in the nervous system (1), and it has also been postulated to play a central role in the marked decline of water ADC in neural tissue following the onset of ischemia (2-4). However, due to hardware limitations, there has been limited direct investigation in vivo of the effects of restrictions on diffusion measurements with MRI. Such observations can be made by measuring ADC as a function of diffusion time.In an NMR diffusion measurement, if the time allowed for spins to migrate is brief enough, restriction will have little impact on the measurement and the ADC will closely reflect the intrinsic diffusion coefficient. As the diffusion time increases and the molecules interact more often with the physical restrictions, the ADC declines toward an asymptotic value. Several such measurements have been made on excised tissue samples (5-9), typically using spectrometers equipped with strong gradients (50 -500 gauss/cm), which allow ADC measurements at relatively short diffusion times.In vivo measurements, however, have been limited by gradient strengths that are typically one or two orders of magnitude smaller, making the minimal diffusion time relatively long. In RIF-1 tumors, Helmer et al. (10) fou...

Recent advancements in MRI have enabled clinical imaging of human cortical bone, providing a potentially powerful new means for assessing bone health with molecular-scale sensitivities unavailable to conventional X-ray-based diagnostics. In human cortical bone, MRI is sensitive to populations of protons ( 1 H) partitioned among water and protein sources, which may be differentiated according to intrinsic NMR properties such as chemical shift and transverse and longitudinal relaxation rates. Herein, these NMR properties were assessed in human cortical bone donors from a broad age range, and four distinct 1 H populations were consistently identified and attributed to five microanatomical sources. These findings show that modern human cortical bone MRI contrast will be dominated by collagen-bound water, which can also be exploited to study human cortical bone collagen via magnetization transfer. Magn Reson Med 64:680-687,

Polymer gels whose NMR and optical properties change when irradiated offer unique advantages for measuring radiation dose distributions. To date, all acrylic polymer gel dosimeters must be manufactured, stored and irradiated in hypoxic conditions which severely limits their use and stability. A new formulation of acrylic dosimeter gel has been developed that responds well in normal atmosphere and which we have named MAGIC (Methacrylic and Ascorbic acid in Gelatin Initiated by Copper). To produce dosimeter gels, an aqueous solution of gelatin, open to the atmosphere, is mixed with methacrylic acid, copper(II) ions, ascorbic acid and hydroquinone. It is believed that the copper(II) and ascorbic acid form a complex with oxygen which (with radiolysis of water) serves as a free radical source for the initiation of the polymerization of methacrylic acid. At room air the water proton spin relaxation rate R2 in MAGIC gels is proportional to absorbed dose though the precise relationship depends on the composition of the gel and the initiating complex. For example, in the range 0-30 Gy the slope of the response of R2 versus dose at 20 MHz was 0.300, 0.519 and 0.681 s(-1) Gy(-1), respectively, when the concentration of MAA was 3, 6 and 9%. The slopes increased to 0.310, 0.567 and 0.868 s(-1) Gy(-1) at 85 MHz. An important determinant of the sensitivity to detect small dose changes is shown to be the slope-to-intercept ratio of the dose-response curve. These varied from 0.08 to 0.17, comparable to hypoxic gels described earlier. MAGIC gels can be manufactured and used much more easily than the previous formulations and can be imaged by magnetic resonance imaging or optical scanning, and thus they will likely be of considerable interest to radiation physicists.

Advances in modern MRI pulse sequences have enabled clinically-practical cortical bone imaging. Human cortical bone is known to contain a distribution of T1 and T2 components attributed to bound and pore water, although clinical imaging approaches have yet to discriminate bound from pore water on the basis of their relaxation properties. Herein, two clinically-compatible MRI strategies are proposed for selectively imaging either bound or pore water by utilizing differences in their T1s and T2s. The strategies are validated in a population of ex vivo human cortical bones, and estimates obtained for bound and pore water are compared to bone mechanical properties. Results show that the two MRI strategies provide good estimates of bound and pore water that correlate to bone mechanical properties. As such, the strategies for bound and pore water-discrimination shown herein should provide diagnostically useful tools for assessing bone fracture risk, once applied to clinical MRI.

Quantitative MRI measures of multiexponential T 2 relaxation and magnetization transfer were acquired from six samples of excised and fixed rat spinal cord and compared with quantitative histology. MRI and histology data were analyzed from six white matter tracts, each of which possessed unique microanatomic characteristics (axon diameter and myelin thickness, in particular) but a relatively constant volume fraction of myelin. The results indicated that multiexponential T 2 relaxation characteristics varied substantially with variation of microanatomy, while the magnetization transfer characteristics remained close to constant. The most-often-cited multiexponential T 2 relaxation metric, myelin water fraction, varied by almost a factor of 2 between two regions with myelin volume fractions that differed by only % 12%. Based on the quantitative histology, the proposed explanation for this variation was intercompartmental water exchange, which caused the underestimation of myelin water fraction and T 2 values and is, presumably, a greater factor in white matter regions where axons are small and myelin is thin. In contrast to the multiexponential T 2 relaxation observations, magnetization transfer metrics were relatively constant across white matter tracts and concluded to be relatively insensitive to intercompartmental water exchange. Magn Reson Med 63:902-909, 2010. V C 2010 Wiley-Liss, Inc.Key words: MRI; multiexponential T 2 ; magnetization transfer; histology; myelin Multiexponential T 2 (MET 2 ) and quantitative magnetization transfer (qMT) have been proposed as potential MRI-derived reporters of myelin content in white matter (WM) and nerve. With MET 2 , the relative size of shortlived T 2 component (typically, T 2 ¼ 8-50 ms, depending on the amplitude of static field) has been defined as the myelin water fraction (MWF) and interpreted as a direct measure of myelin content (1,2). Similarly, in WM, the macromolecular protons that exchange magnetization with water protons are thought to be substantially constituents of myelin (3,4). That is, the qMT measure of this macromolecular pool size relative to the total water signal, sometimes called the pool-size-ratio (PSR) (5), is believed to be a measure of relative myelin content. While both MWF and PSR have been found to correlate with myelin content when comparing normal myelinated tissue with demyelinated or dysmyelinated tissue (6-11 and many others), the exact relationship between these measures and myelin content is not well understood.The interpretation of MWF as a measure of myelin content is predicated on the assumption of slow exchange between myelin water and water in the intraand interaxonal spaces, referred to herein as other water. If the rate of exchange between myelin water and other water is dependent upon the dimensions of these compartments (i.e., axon diameter [AxD], myelin thickness [MyTh], interaxonal distance), then the slow exchange model may be more suitable in some myelinated tissues than others. For example, peripheral nerve tends to have...

The authors report NMR measurements of the changes in water diffusion brought about by in vivo Wallerian degeneration due to either crush- or tie-injuries in the sciatic nerve of the frog. Using a pulsed-gradient spin-echo sequence with a diffusion measurement time of 28 ms, the degree of diffusion coefficient anisotropy ¿D(longitudinal)/D(transverse)¿ 4 weeks after injury in both crush- and tie-injured nerves (2.3 +/- 0.4 and 1.7 +/- 0.1, respectively) is significantly less than in normal frog sciatic nerve (3.9 +/- 0.4). The decrease of anisotropy in the degenerated nerves is due to both a decrease in longitudinal diffusion and an increase in transverse diffusion. The changes in diffusion coefficients are compared with the degree of axonal and myelin breakdown observed in light and electron micrographs of the nerves.

Comprising ~20% of the volume, water is a key determinant of the mechanical behavior of cortical bone. It essentially exists in 2 general compartments: within pores and bound to the matrix. The amount of pore water – residing in vascular-lacunar-canalicular space – primarily reflects intracortical porosity (i.e., open spaces within the matrix largely due to Haversian canals and resorption sites), and as such, is inversely proportional to most mechanical properties of bone. Movement of water according to pressure gradients generated during dynamic loading likely confers hydraulic stiffening to the bone as well. Nonetheless, bound water is a primary contributor to mechanical behavior of bone in that it is responsible for giving collagen the ability to confer ductility or plasticity to bone (i.e., allows deformation to continue once permanent damage begins to form in the matrix) and decreases with age along with fracture resistance. Thus, dehydration by air-drying or by solvents with less hydrogen bonding capacity causes bone to become brittle, but interestingly, it also increases stiffness and strength across the hierarchical levels of organization. Despite the importance of matrix hydration to fracture resistance, little is known about why bound water decreases with age in hydrated human bone. Using 1H nuclear magnetic resonance (NMR), both bound and pore water concentrations in bone can be measured ex vivo because the proton relaxation times differ between the two water compartments giving rise to two distinct signals. There are also emerging techniques to measure bound and pore water in vivo with magnetic resonance imaging (MRI). NMR/MRI-derived bound water concentration is positively correlated with both strength and toughness of hydrated bone, and may become a useful clinical marker of fracture risk.