Relaxation of protons by radicals in rotationally immobilized proteins

Proton spin-lattice relaxation by paramagnetic centers may be dramatically enhanced if the paramagnetic center is rotationally immobilized in the magnetic field. The details of the relaxation mechanism are different from those appropriate to solutions of paramagnetic relaxation agents. We report here large enhancements in the proton spin-lattice relaxation rate constants associated with organic radicals when the radical system is rigidly connected with a rotationally immobilized macromolecular matrix such as a dry protein or a cross-linked protein gel. The paramagnetic contribution to the protein-proton population is direct and distributed internally among the protein protons by efficient spin diffusion. In the case of a cross-linked-protein gel, the paramagnetic effects are carried to the water spins indirectly by chemical exchange mechanisms involving water molecule exchange with rare long-lived water molecule binding sites on the immobilized protein and proton exchange. The dramatic increase in the efficiency of spin relaxation by organic radicals compared with metal systems at low magnetic field strengths results because the electron relaxation time of the radical is orders of magnitude larger than that for metal systems. This gain in relaxation efficiency provides completely new opportunities for the design of spin-lattice relaxation based contrast agents in magnetic imaging and also provides new ways to examine intramolecular protein dynamics.     

Bayesian Modeling of NMR Data: Quantifying Longitudinal Relaxation in Vivo,and in Vitro with a Tissue-Water-Relaxation Mimic (Crosslinked Bovine Serum Albumin)

Recently, a number of magnetic resonance imaging protocols have been reported that seek to exploit the effect of dissolved oxygen (O₂, paramagnetic) on the longitudinal ¹H relaxation of tissue water, thus providing image contrast related to tissue oxygen content. However, tissue water relaxation is dependent on a number of mechanisms and this raises the issue of how best to model the relaxation data. This problem, the model selection problem, occurs in many branches of science and is optimally addressed by Bayesian probability theory. High signal-to-noise, densely sampled, longitudinal ¹H relaxation data were acquired from rat brain in vivo and from a cross-linked bovine serum albumin (xBSA) phantom, a sample that recapitulates the relaxation characteristics of tissue water in vivo. Bayesian-based model selection was applied to a cohort of five competing relaxation models: (1) monoexponential, (2) stretched-exponential, (3) biexponential, (4) Gaussian (normal) R ₁-distribution, and (5) gamma R ₁-distribution. Bayesian joint analysis of multiple replicate datasets revealed that water relaxation of both the xBSA phantom and in vivo rat brain was best described by a biexponential model, while xBSA relaxation datasets truncated to remove evidence of the fast relaxation component were best modeled as a stretched exponential. In all cases, estimated model parameters were compared to the commonly used monoexponential model. Reducing the sampling density of the relaxation data and adding Gaussian-distributed noise served to simulate cases in which the data are acquisition-time or signal-to-noise restricted, respectively. As expected, reducing either the number of data points or the signal-to-noise increases the uncertainty in estimated parameters and, ultimately, reduces support for more complex relaxation models.     

MR pulse sequences for selective relaxation time measurements: a phantom study

The accuracy of relaxation time measurements of spectroscopic inversion recovery and CPMG multi-echo pulse sequences together with ISIS and stimulated echo-pulse methods have been tested on a reference phantom (test object no. 5, of the EEC Concerted Research Project). For the measurements a Siemens Magnetom wholebody magnetic resonance scanner operating at 1.5 Tesla was used. For comparison six imaging pulse sequences for relaxation time measurements were tested on the same phantom. The spectroscopic pulse sequences all had an accuracy better than 10% of the reference values.     

On the strong field dependence and nonlinear response to gadolinium contrast agent of proton transverse relaxation rates in dairy cream

Dairy cream, as a suspension of lipid droplets in water, is a potentially useful magnetic resonance imaging (MRI) phantom material and an interesting material for studying fundamental relaxation mechanisms. Here we report a strong increase in the transverse relaxation rates with field strength for both the water and lipid protons in dairy cream. Also, studies at 4.7 T reveal a nonlinear response of transverse relaxation rates with increasing concentration of a common gadolinium (Gd)-based contrast agent, including an initial decrease of water relaxation rates as measured with Hahn spin echoes at the lower Gd concentrations. The results are treated within the framework of a model in which the magnetic susceptibility difference between the lipid droplets and the aqueous phase plays the prominent role for transverse relaxation. Second-order polynomial fits of the water proton transverse relaxation rate dependence on field strength and on Gd concentration at 4.7 T provided experimental parameters from which model parameters are extracted and compared with expectations available from the literature.     

Imaging contrast effects in alginate microbeads containing trapped emulsion droplets

This study focuses on spherical microparticles made of cross-linked alginate gel and microcapsules composed of an oil-in-water emulsion where the continuous aqueous phase is cross-linked into an alginate gel matrix. We have investigated the use of these easily manufactured microbeads as contrast agents for the study of the flow properties of fluids using nuclear magnetic resonance imaging. Results demonstrate that combined spin-spin (T(2)) relaxation and diffusion contrast in proton NMR imaging can be used to distinguish among rigid polymer particles, plain alginate beads, and alginate emulsion beads. Multi-echo CPMG spin-echo imaging indicates that the average spin-lattice (T(1)) and spin-spin (T(2)) relaxation times of the plain alginate and alginate emulsion beads are comparable. Meanwhile, diffusion-weighted imaging produces sharp contrast between the two types of alginate beads, due to restricted diffusion inside the embedded oil droplets of the alginate emulsion beads. While the signal obtained from most materials is severely attenuated under applied diffusion gradients, the alginate emulsion beads maintain signal strength. The alginate emulsion beads were added to a suspension and imaged in an abrupt, annular expansion flow. The emulsion beads could be clearly distinguished from the surrounding suspending fluid and rigid polystyrene particles, through either T(2) relaxation or diffusion contrast. Such a capability allows future use of the alginate emulsion beads as tracer particles and as one particle type among many in a multimodal suspension where detailed concentration profiles or particle size separation must be quantified during flow.     

Efficiency of paramagnetic relaxation enhancement in off-resonance rotating frame

Transferring from laboratory frame to off-resonance rotating frame for the (1)H spin can compensate the relaxivity loss for paramagnetic agents at the magnetic field strength higher than 3 Tesla and enhance water relaxation rate constant significantly. A comprehensive theory for calculating the relaxation rate constants in the off-resonance rotating frame is described. This theory considers the contributions from both inner shell and outer shell water. The derived relaxation rate constants and relaxation enhancement efficiency as a function of the magnetic field strength and the effective field parameters are directly correlated to the structures, dynamics and environments of paramagnetic agents. To validate the theoretical predictions, we have measured the relaxation enhancement efficiency for a series of macromolecule conjugated gadolinium chelates at 9.4 Tesla. The experimental results confirmed the theoretical predictions. The theory also predicts the relaxation enhancement for T(2)-type paramagnetic agents at high magnetic fields. Promising fields of applications include situations where T(1)- or T(2)-type paramagnetic agents are used for labeling molecular/cellular events.     

Assessment of scanner performance and normalization of estimated relaxation rate values

The purpose of this study was to develop and test a method for the assessment of Magnetic Resonance (MR) scanner performance suitable for routine brain MR studies and for normalization of calculated relaxation times. We hypothesized that regular monitoring of machine performance changes could provide a helpful normalization tool for calculating tissue MR parameters, thus contributing to support their use for longitudinal and comparative studies of both normal and diseased tissues.The method is based on the acquisition of phantom images during routine brain studies with standard spin-echo sequences. MR phantom and brain tissue parameters were used to assess the influence of machine related changes on relaxation parameter estimates. Experimental results showed that scanner performance may affect relaxation rate estimates. Phantom and in vivo results indicate that the correction method yields a reduction in variability of estimated phantom R1 values up to 29% and of R1 for different brain structures up to 17%. These findings support the validity of using brain coil phantoms for routine system monitoring and correction of tissue relaxation rates.     

Water diffusion-exchange effect on the paramagnetic relaxation enhancement in off-resonance rotating frame

The off-resonance rotating frame technique based on the spin relaxation properties of off-resonance T1rho can significantly increase the sensitivity of detecting paramagnetic labeling at high magnetic fields by MRI. However, the in vivo detectable dimension for labeled cell clusters/tissues in T1rho-weighted images is limited by the water diffusion-exchange between mesoscopic scale compartments. An experimental investigation of the effect of water diffusion-exchange between compartments on the paramagnetic relaxation enhancement of paramagnetic agent compartment is presented for in vitro/in vivo models. In these models, the size of paramagnetic agent compartment is comparable to the mean diffusion displacement of water molecules during the long RF pulses that are used to generate the off-resonance rotating frame. The three main objectives of this study were: (1) to qualitatively correlate the effect of water diffusion-exchange with the RF parameters of the long pulse and the rates of water diffusion, (2) to explore the effect of water diffusion-exchange on the paramagnetic relaxation enhancement in vitro, and (3) to demonstrate the paramagnetic relaxation enhancement in vivo. The in vitro models include the water permeable dialysis tubes or water permeable hollow fibers embedded in cross-linked proteins gels. The MWCO of the dialysis tubes was chosen from 0.1 to 15 kDa to control the water diffusion rate. Thin hollow fibers were chosen to provide sub-millimeter scale compartments for the paramagnetic agents. The in vivo model utilized the rat cerebral vasculatures as a paramagnetic agent compartment, and intravascular agents (Gd-DTPA)30-BSA were administrated into the compartment via bolus injections. Both in vitro and in vivo results demonstrate that the paramagnetic relaxation enhancement is predominant in the T1rho-weighted image in the presence of water diffusion-exchange. The T1rho contrast has substantially higher sensitivity than the conventional T1 contrast in detecting paramagnetic agents, especially at low paramagnetic agent volumetric fractions, low paramagnetic agent concentrations, and low RF amplitudes. Short pulse duration, short pulse recycle delay and efficient paramagnetic relaxation can reduce the influence of water diffusion-exchange on the paramagnetic enhancement. This study paves the way for the design of off-resonance rotating experiments to detect labeled cell clusters/tissue compartments in vivo at a sub-millimeter scale.     

Phantom materials for single point imaging pulse sequences

The popularity of pure phase encode MRI techniques, including single point imaging (SPI), is steadily increasing, particularly in instances where the samples of interest are solid-like, or for other reasons possess short effective transverse relaxation times, T2*. As the interest in these techniques grows, so too does the need for a phantom material which is representative of this class of samples. The characteristics of such a phantom should include chemical and physical stability, straightforward preparation, high signal to noise ratio and relaxation times which are both easily manipulated and representative. To this end, we have developed a gelatin/sucrose-based gel which addresses the above criteria and behaves as a very flexible short T2* phantom. An order of magnitude variation in T1 and T2 can be achieved over a reasonable range of sucrose concentration. Even larger changes can be achieved with the addition of further doping agents.     

Assessment of the biomechanical state of intracranial tissues by dynamic MRI of cerebrospinal fluid pulsations: a phantom study

We used a cranial phantom to investigate how intracranial mechanical factors [brain compliance and the resistance to the flow of cerebrospinal fluid (CSF)] affect the way in which CSF pulsations are driven by pulsatile transcranial blood flow. Dynamic phase-contrast magnetic resonance imaging (MRI) was used to measure the transfer function between vascular pulsations and pulsatile response of the CSF below the foramen magnum of the phantom. We found that the coupling between the high frequency components of cervical CSF flow and transcranial blood flow was decreased when the phantom was modified to simulate increased brain compliance and increased resistance to CSF flow.     

Frequency-shift based detection of BMS contrast agents using SSFP: potential for MRA

A novel mechanism of MRI contrast enhancement, based on the detection by a balanced steady-state free precession (SSFP) sequence of the proton resonance frequency shift induced by bulk magnetic susceptibility (BMS) contrast agents, was investigated. The potential for this contrast mechanism to image blood vessels was explored. The relaxation time and the frequency shift effects of gadolinium- and dysprosium-DOTA on SSFP signal was first simulated and evaluated on a water phantom at 1.5 T. In vitro, a 5-mM concentration in contrast agent induced a 20-Hz frequency shift, leading to a signal increase of 92% for Dy-DOTA, and a 10-Hz frequency shift, leading to a signal increase of 58% for Gd-DOTA at the reference frequency, taking into account the nonlinear SSFP signal response on frequency offset. The concept was then evaluated in vivo on anesthetized rabbits. Low doses of dysprosium-DOTA were injected in their vascular system, and imaging was performed at the level of neck vessels. Following a bolus injection, mean signal changes of 31%, 20% and 14% were observed in the carotid arteries, the vertebral veins and the jugular veins, respectively. The bolus peak times in arteries and veins were consistent with the rabbit vascular circulation. This frequency-shift based contrast mechanism presents interesting potential for contrast-enhanced MR angiography (CE-MRA) compared to usual relaxation-based contrast, but further investigations on reproducibility will be necessary.     

Point-wise measurements of MRS volume selection performance are insensitive to magnetic susceptibility effects of phantom materials

The purpose was to analyse magnetic susceptibility effects on accuracy of point-wise measurements of signal profiles in the assessment of MRS volume selection performance. An existing phantom design consisting of a sphere with a movable signal source was used for the investigation. The influence from the phantom on magnetic field homogeneity was measured with phase sensitive 1H imaging and 31P spectroscopy on a 1.5 T whole body MR system. The susceptibility effects for such a phantom design can be separated in 1/ A variation in the background magnetic field, which is caused by the stationary structures and has a significant influence on spatial accuracy. 2/ A magnetic field distortion, which is caused by the movable signal source and has very little influence on accuracy. The spatial inaccuracy due to susceptibility effects in this phantom, was 0.03 mm for positions of the signal source covering a 40-mm VOI. Susceptibility effects from the movable signal source were substantial but had very little influence on spatial accuracy. Still, improvements of this phantom design are possible. Point-wise measurements using a phantom with a movable signal source is inherently insensitive to susceptibility effects from the signal source and permits accurate signal profile measurements of high spatial (sub-mm) resolution.     

Determination of Very Slow Diffusion of Paramagnetic Ions by NMR Spectroscopy

In this paper, we propose a new method of measuring the very slow paramagnetic ion diffusion coefficient using a commercial high-resolution spectrometer. If there are distinct paramagnetic ions influencing the hydrogen nuclear magnetic relaxation time differently, their diffusion coefficients can be measured separately. A cylindrical phantom filled with Fricke xylenol gel solution and irradiated with gamma rays was used to validate the method. The Fricke xylenol gel solution was prepared with 270 Bloom porcine gelatin, the phantom was irradiated with gamma rays originated from a ⁶⁰Co source and a high-resolution 200 MHz nuclear magnetic resonance (NMR) spectrometer was used to obtain the phantom ¹H profile in the presence of a linear magnetic field gradient. By observing the temporal evolution of the phantom NMR profile, an apparent ferric ion diffusion coefficient of 0.50 μm²/ms due to ferric ions diffusion was obtained. In any medical process where the ionizing radiation is used, the dose planning and the dose delivery are the key elements for the patient safety and success of treatment. These points become even more important in modern conformal radio therapy techniques, such as stereotactic radiosurgery, where the delivered dose in a single session of treatment can be an order of magnitude higher than the regular doses of radiotherapy. Several methods have been proposed to obtain the three-dimensional (3-D) dose distribution. Recently, we proposed an alternative method for the 3-D radiation dose mapping, where the ionizing radiation modifies the local relative concentration of Fe²⁺/Fe³⁺ in a phantom containing Fricke gel and this variation is associated to the MR image intensity. The smearing of the intensity gradient is proportional to the diffusion coefficient of the Fe³⁺ and Fe²⁺ in the phantom. There are several methods for measurement of the ionic diffusion using NMR, however, they are applicable when the diffusion is not very slow.     

High-frequency stress relaxation in semiflexible polymer solutions and networks

We measure the linear viscoelasticity of sterically entangled and chemically cross-linked networks of actin filaments over more than five decades of frequency. The high-frequency response reveals rich dynamics unique to semiflexible polymers, including a previously unobserved relaxation due to rapid axial tension propagation. For high molecular weight, and for cross-linked gels, we obtain quantitative agreement with predicted shear moduli in both amplitude and frequency dependence.     

On the influence of two coexisting species of susceptibility-producing structures on the R21 relaxation rate

PurposeTissue microstructure can influence quantitative magnetic resonance imaging such as relaxation rate measurements. Consequently, relaxation rate mapping can provide useful information on tissue microstructure. In this work, the theory on relaxation mechanisms of the change of the relaxation rate ∆R₂^⁎ in the presence of spherical susceptibility sources in a spin bearing medium is validated in simulations and phantom experiments for the coexistence of two species of susceptibility sources.MethodsThe influence of coexisting spherical perturbers with magnetic susceptibilitys of different signs was evaluated in Monte Carlo simulations including diffusion effects in the surrounding medium. Simulations were compared with relaxometry measurements at 1.5 Tesla and at 3 Tesla. The phantoms used to validate the simulations were built from agarose gel containing calcium carbonate and tungsten carbide particles of different size and concentration.ResultsThe Monte Carlo simulations showed, that the change in relaxation rate only depends on the overall amount of susceptibility producing structures in the simulation volume and no difference was found, if mixtures of positive and negative particles were simulated. Phantom measurements within the static dephasing regime showed linear additivity of the effects from positive and negative susceptibility sources that were present within the same voxel.ConclusionsIn summary, both the simulations and the phantom measurements showed that changes in the relaxation rate ΔR₂^⁎ add up linearly for spherical particles with different susceptibilities within the same voxel if the conditions for the static dephasing regime are fulfilled. If particles with different susceptibilities have both different sizes and violate the conditions of the static dephasing regime, effects on relaxation rates might no longer be linear.     

Screening and in-plane magnetoresistance of an anisotropic two-dimensional gas

In order to split the influence of the orbital and spin effects on the in-plane magnetoresistance of a quasi-two-dimensional (2D) gas, we derive its linear response function and dielectric function for the case of anisotropic effective mass. This result is used for the calculation of elastic transport relaxation time of a quasi-two-dimensional system in a parallel magnetic field. The relaxation time is proved to be isotropic in the low-density limit for the case of charged impurity scattering, allowing us to separate the two contributions.     

Oxygen-sensitive 19F NMR imaging of the vascular system in vivo

The fluorine nuclear magnetic resonance spin-lattice relaxation rate (1/T1) of the perfluorochemical blood substitute perfluorotripropylamine (FTPA) is very sensitive to oxygen tension. This presents the possibility of measuring blood oxygen tension by 19F MR imaging. We obtained oxygen-sensitive 19F NMR images of the circulatory system of rats infused with emulsified FTPA. Blood oxygenation was assessed under conditions of both air- and 100% O2-breathing. T1 relaxation times were derived from MR images using a partial saturation pulse sequence. The T1 times were compared with a phantom calibration curve to calculate average blood pO2 values in the lung, liver, and spleen. The results showed marked, organ-specific increases in blood oxygen tension when the rat breathed 100% O2 instead of air.     

Fast 3D coronary artery contrast-enhanced magnetic resonance angiography with magnetization transfer contrast, fat suppression and parallel imaging as applied on an anthropomorphic moving heart phantom

A magnetic resonance sequence for high-resolution imaging of coronary arteries in a very short acquisition time is presented. The technique is based on fast low-angle shot and uses fat saturation and magnetization transfer contrast prepulses to improve image contrast. GeneRalized Autocalibrating Partially Parallel Acquisitions (GRAPPA) is implemented to shorten acquisition time. The sequence was tested on a moving anthropomorphic silicone heart phantom where the coronary arteries were filled with a gadolinium contrast agent solution, and imaging was performed at varying heart rates using GRAPPA. The clinical relevance of the phantom was validated by comparing the myocardial relaxation times of the phantom's homogeneous silicone cardiac wall to those of humans. Signal-to-noise ratio and contrast-to-noise ratio were higher when parallel imaging was used, possibly benefiting from the acquisition of one partition per heartbeat. Another advantage of parallel imaging for visualizing the coronary arteries is that the entire heart can be imaged within a few breath-holds.     

Continuous wave MRI of heterogeneous materials

A prototype continuous wave MRI system operating at 7T has been used successfully to study a variety of heterogeneous materials exhibiting T2 relaxation values ranging from 10 micros to 50 ms. Two-dimensional images of a poly(methly methacrylate) (PMMA) resolution phantom (T2=38 micros) exhibited a spatial resolution of approximately 1mm at a magnetic field gradient strength of 200 mT/m. The technique was used to study the hydration, drying, and subsequent water penetration properties of cement samples made from ordinary Portland cement, and revealed inhomogeneities arising from the cure conditions. Sandstone samples from an oil reservoir in the North Sea were also studied; structure within these materials, arising from the sedimentary bed layering in the reservoir, was found to have an effect on their water transport properties. A section from a confectionery bar (T2* approximately 50-60 ms) was also imaged, and its internal structure could be clearly discerned.