Mark D. Does

Polymer gels for magnetic resonance imaging of radiation dose distributions at normal room atmosphere.

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.

Oscillating gradient measurements of water diffusion in normal and globally ischemic rat brain

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 μs, 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 micro‐anatomy 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 μm, similar to a typical cellular dimension in gray matter. Magn Reson Med 49:206–215, 2003.

Compartmental study of T1 and T2 in rat brain and trigeminal nerve in vivo

The integrated T1–T2 characteristics of rat brain and trigeminal nerve water were studied in vivo using a rapid method for acquiring a series of images that depend on T1 and T2 relaxation times. Gray matter regions showed only one signal component in both the T1 and T2 domains. Trigeminal nerve, however, which has been shown previously to exhibit three T2 components, was found to also exhibit three T1 components. The correlations between these T1 and T2 components were demonstrated by uniquely filtering out each of the three T2 components using an inversion‐recovery preparation, as determined by the component T1 values. Based on previous works, it is postulated that each of these three signal components is derived from a unique microanatomical region of the nerve. Knowledge of these T1 components may thus prove valuable in devising novel methods of identifying the presence and quantifying the volume of tissue subtypes such as myelin. Magn Reson Med 47:274–283, 2002.

Characterization of 1H NMR Signal in Human Cortical Bone for Magnetic Resonance Imaging

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 (1H) 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 1H 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, 2010.

Multiexponential T2, magnetization transfer, and quantitative histology in white matter tracts of rat spinal cord.

Quantitative MRI measures of multiexponential T2 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 T2 relaxation characteristics varied substantially with variation of microanatomy, while the magnetization transfer characteristics remained close to constant. The most‐often‐cited multiexponential T2 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 T2 values and is, presumably, a greater factor in white matter regions where axons are small and myelin is thin. In contrast to the multiexponential T2 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.

Characterization of tissue structure at varying length scales using temporal diffusion spectroscopy

The concepts, theoretical behavior and experimental applications of temporal diffusion spectroscopy are reviewed and illustrated. Temporal diffusion spectra are obtained using oscillating‐gradient waveforms in diffusion‐weighted measurements, and represent the manner in which various spectral components of molecular velocity correlations vary in different geometrical structures that restrict or hinder free movements. Measurements made at different gradient frequencies reveal information on the scale of restrictions or hindrances to free diffusion, and the shape of a spectrum reveals the relative contributions of spatial restrictions at different distance scales. Such spectra differ from other so‐called diffusion spectra which depict spatial frequencies and are defined at a fixed diffusion time. Experimentally, oscillating gradients at moderate frequency are more feasible for exploring restrictions at very short distances which, in tissues, correspond to structures smaller than cells. We describe the underlying concepts of temporal diffusion spectra and provide analytical expressions for the behavior of the diffusion coefficient as a function of gradient frequency in simple geometries with different dimensions. Diffusion in more complex model media that mimic tissues has been simulated using numerical methods. Experimental measurements of diffusion spectra have been obtained in suspensions of particles and cells, as well as in vivo in intact animals. An observation of particular interest is the increased contrast and heterogeneity observed in tumors using oscillating gradients at moderate frequency compared with conventional pulse gradient methods, and the potential for detecting changes in tumors early in their response to treatment. Computer simulations suggest that diffusion spectral measurements may be sensitive to intracellular structures, such as nuclear size, and that changes in tissue diffusion properties may be measured before there are changes in cell density. Copyright

In vivo measurement of ADC change due to intravascular susceptibility variation.

The apparent diffusion coefficient (ADC) of extravascular tissue water in rat brains was measured in response to step‐wise injections of the superparamagnetic intravascular contrast agent AMI‐227. These data were normalized and compared with measured changes in R*2 and blood magnetic susceptibility. Linear regression showed that ADC changes 33%/ppm shift of intravascular susceptibility and 0.43% s−1 change in R*2. These changes correspond to a predicted ADC change of ≈ 6% for a change between fully oxygenated and fully deoxygenated blood. The source of these ADC changes was confirmed to be background gradients within the sample by the use of diffusion weighting with bipolar gradients of odd symmetry designed to cancel such background gradient effects on ADC. The results suggest that diffusion‐weighted imaging is sensitive to blood‐oxygenation and may provide a means of measuring changes in blood oxygen. They also provide estimates of the potential contribution of susceptibility changes to changes in ADC that occur, for example, in stroke and seizure. Magn Reson Med 41:236–240, 1999.

Multi-angle ratiometric approach to measure chemical exchange in amide proton transfer imaging

Amide proton transfer imaging, a specific form of chemical exchange saturation transfer imaging, has previously been applied to studies of acute ischemic acidosis, stroke, and cancer. However, interpreting the resulting contrast is complicated by its dependence on the exchange rate between amides and water, the amide concentration, amide and water relaxation, and macromolecular magnetization transfer. Hence, conventional chemical exchange saturation transfer contrast is not specific to changes such as reductions in pH due to tissue acidosis. In this article, a multi‐angle ratiometric approach based on several pulsed‐chemical exchange saturation transfer scans at different irradiation flip angles is proposed to specifically reflect exchange rates only. This separation of exchange effects in pulsed‐chemical exchange saturation transfer experiments is based on isolating rotation vs. saturation contributions, and such methods form a new subclass of chemical exchange rotation transfer (CERT) experiments. Simulations and measurements of creatine/agar phantoms indicate that a newly proposed imaging metric isolates the effects of exchange rate changes, independent of other sample parameters. Magn Reson Med, 2012.

Optimizing pulsed-chemical exchange saturation transfer imaging sequences

Chemical exchange saturation transfer (CEST) provides a new imaging contrast mechanism sensitive to labile proton exchange. Pulsed‐CEST imaging is better suited to the hardware constraints on clinical imaging systems when compared with traditional continuous wave‐CEST imaging methods. However, designing optimum pulsed‐CEST imaging sequences entails complicated and time‐consuming numerical integrations. In this work, a simplified and computationally efficient technique is provided to optimize the pulsed‐CEST imaging sequence. An analysis was performed of the optimal average irradiation power and the optimal irradiation flip angle as a function of the acquisition parameters and sample properties in both a two‐pool model and a three‐pool model of endogenous amine exchange. Key simulated and experimental results based on a creatine/agar tissue phantom show that ( 1 ) the average irradiation power is a more meaningful sequence metric than is the average irradiation field amplitude, ( 2 ) the optimal average powers for continuous wave and pulsed‐CEST imaging are approximately equal to each other for a relevant range of solute frequency offsets, exchange rates, and concentrations, ( 3 ) an irradiation flip angle of 180° is optimal or near optimal, independent of the other acquisition parameters and the sample properties, and ( 4 ) higher duty cycles yield higher CEST contrast. Magn Reson Med, 2011.

A new method for detecting exchanging amide protons using chemical exchange rotation transfer

In this study, we introduce a new method for amide proton transfer imaging based on chemical exchange rotation transfer. It avoids several artifacts that plague conventional chemical exchange saturation transfer approaches by creating label and reference scans based on varying the irradiation pulse rotation angle (π and 2π radians) instead of the frequency offset (3.5 and −3.5 ppm). Specifically, conventional analysis is sensitive to confounding contributions from magnetic field (B0) inhomogeneities and, more problematically, inherently asymmetric macromolecular resonances. In addition, the lipid resonance at −3.5 ppm complicates the interpretation of the reference scan and decreases the resulting contrast. Finally, partial overlap of the amide signal by nearby amines and hydroxyls obscure the results. By avoiding these issues, our new method is a promising approach for imaging endogenous protein and peptide content and mapping pH. Magn Reson Med, 2013.