Feasibility of using a single MRI acquisition for fiducial marker localization and synthetic CT generation towards MRI-only prostate radiation therapy treatment planning.

Purpose.To investigate the feasibility of using a single MRI acquisition for fiducial marker identification and synthetic CT (sCT) generation towards MRI-only treatment planning for prostate external beam radiation therapy (EBRT).Methods.Seven prostate cancer patients undergoing EBRT, each with three implanted gold fiducial markers, participated in this study. In addition to the planning CT scan, all patients were scanned on a 3 T MR scanner with a 3D double-echo gradient echo (GRE) sequence. Quantitative susceptibility mapping (QSM) was performed for marker localization. QSM-derived marker positions were compared to those from CT. The bulk density assignment technique for sCT generation was adopted. The magnitude GRE images were segmented into muscle, bone, fat, and air using a combination of unsupervised intensity-based classification of soft tissue and convolutional neural networks (CNN) for bone segmentation.Results.All implanted markers were visualized and accurately identified (average error: 0.7 ± 0.5 mm). QSM generated distinctive contrast for hemorrhage, calcifications, and gold fiducial markers. The estimated susceptibility/HU values on QSM/CT for gold and calcifications were 31.5 ± 2.9 ppm/1220 ± 100 HU and 14.6 ± 0.9 ppm/440 ± 100 HU, respectively. The intensity-based soft tissue classification resulted in an average Dice score of 0.97 ± 0.02; bone segmentation using CNN resulted in an average Dice score of 0.93 ± 0.03.Conclusion.This work indicates the feasibility of simultaneous fiducial marker identification and sCT generation using a single MRI acquisition. Future works includes evaluation of the proposed method in a large cohort of patients with optimized acquisition parameters as well as dosimetric evaluations.

Gene delivery to the spinal cord using MRI-guided focused ultrasound.

Non-invasive gene delivery across the blood-spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury and disease. Here, we demonstrate the use of magnetic resonance image-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats at three dosages: 4 × 10(8), 2 × 10(9) and 7 × 10(9) vector genomes per gram (VG g(-1)). MRIgFUS allowed for transient, targeted permeabilization of the BSCB through the interaction of focused ultrasound (FUS) with systemically injected Definity lipid-shelled microbubbles. Viral delivery at 2 × 10(9) and 7 × 10(9) VG g(-1) leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 × 10(9) VG g(-1), GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a non-invasive manner.

In vitro detection of apoptosis using oscillating and pulsed gradient diffusion magnetic resonance imaging.

Cellular apoptosis, a common pathway towards tumor regression, is induced by many radiotherapy and chemotherapy regimens. Imaging methods that can detect apoptosis may be able to assess treatment response earlier than typical tumor volume measurements. In this paper, a wide range of diffusion experiments and a simple model of diffusion in tissues were used to probe the microstructural effects of apoptosis. Experiments were conducted on acute myeloid leukemia cell pellets, where apoptosis was induced by treatment with the chemotherapeutic agent cisplatin. Seventy-two hours following cisplatin treatment, pulsed and oscillating gradient diffusion measurements were utilized to assess effects across a broad range of structural scales. The presence of apoptosis, which was histologically confirmed by TUNEL (terminal deoxynucleotidyl transferase UTP nick end labelling) staining, significantly changed diffusion properties. To describe these changes, the data were fit to the parallel plane model, which characterizes the effects of restricted diffusion in terms of three parameters: d, the restricted size, Dfree , the intrinsic, free diffusion coefficient of the solvent, and Drest , the long time or "restricted" diffusion coefficient. Apoptotic samples exhibited significant decreases in parameters d and Dfree and a significant increase in Drest . These changes appear consistent with the established morphological effects of apoptosis. In particular, the decrease in d may be a result of the combined effects of cell shrinkage, nuclear fragmentation and membrane blebbing, the decrease in Dfree may relate to cytosolic condensation, while the increase in Drest can be attributed to increased membrane permeability and extracellular volume fraction. By non-invasively detecting apoptosis, the methods reported in this study have the potential to improve upon current MRI methods for monitoring therapeutic response. Furthermore, these methods may offer sufficient specificity to differentiate between apoptosis and other modes of cell death, such as oncosis or necrosis.

Effectiveness of micron-sized superparamagnetic iron oxide particles as markers for detection of migration of bone marrow-derived mesenchymal stromal cells in a stroke model.

PURPOSE: To evaluate the feasibility of using micron-sized superparamagnetic iron oxide particles (MPIOs) as an effective labeling agent for monitoring bone marrow-derived mesenchymal stromal cell (BMSC) migration in the brain using magnetic resonance imaging (MRI) in a rat model of stroke and whether the accumulation of MPIO-labeled BMSCs can be differentiated from the accumulation of free MPIO particles or hemoglobin breakdown at a site of neuronal damage. MATERIALS AND METHODS: In this study BMSCs were labeled with iron oxide and their pattern of migration following intravenous injection in a rat stroke model was monitored using a clinical MRI system followed by standard histopathology. The migration pattern was compared between intravenous injection of BMSCs alone, BMSCs labeled with MPIOs, and MPIO particles alone. RESULTS: The results demonstrated that while MRI was highly sensitive in the detection of iron oxide particle-containing cells in areas of neuronal ischemia, the true origin of cells containing iron oxide particles remains ambiguous. Therefore, detection of iron particles may not be a suitable strategy for the detection of BMSCs in the brain in a stroke model. CONCLUSION: This study suggests that the use of MPIOs as labeling agents are insufficient to conclusively determine the localization of iron within cells in regions of neuronal ischemia and hemorrhage.

Oscillating and pulsed gradient diffusion magnetic resonance microscopy over an extended b-value range: implications for the characterization of tissue microstructure.

Oscillating gradient spin-echo (OGSE) pulse sequences have been proposed for acquiring diffusion data with very short diffusion times, which probe tissue structure at the subcellular scale. OGSE sequences are an alternative to pulsed gradient spin echo measurements, which typically probe longer diffusion times due to gradient limitations. In this investigation, a high-strength (6600 G/cm) gradient designed for small-sample microscopy was used to acquire OGSE and pulsed gradient spin echo data in a rat hippocampal specimen at microscopic resolution. Measurements covered a broad range of diffusion times (TDeff = 1.2-15.0 ms), frequencies (ω = 67-1000 Hz), and b-values (b = 0-3.2 ms/µm2). Variations in apparent diffusion coefficient with frequency and diffusion time provided microstructural information at a scale much smaller than the imaging resolution. For a more direct comparison of the techniques, OGSE and pulsed gradient spin echo data were acquired with similar effective diffusion times. Measurements with similar TDeff were consistent at low b-value (b < 1 ms/µm(2) ), but diverged at higher b-values. Experimental observations suggest that the effective diffusion time can be helpful in the interpretation of low b-value OGSE data. However, caution is required at higher b, where enhanced sensitivity to restriction and exchange render the effective diffusion time an unsuitable representation. Oscillating and pulsed gradient diffusion techniques offer unique, complementary information. In combination, the two methods provide a powerful tool for characterizing complex diffusion within biological tissues.

Can MTR be used to assess cartilage in the presence of Gd-DTPA2-?

Magnetization transfer (MT) and T(1) and T(2) relaxation of normal, trypsinized, and interleukin-1beta (IL-1beta)-treated cartilage were measured in the absence and presence of Gd-DTPA(2-). Without the addition of Gd-DTPA(2-), neither T(1) nor T(2) showed any significant change with cartilage damage. However, with Gd-DTPA(2-), trypsinized cartilage exhibited substantially shorter T(1) than normal cartilage, as expected due to the glycosaminoglycan (GAG) loss in these samples, and associated increased Gd-DTPA(2-) concentration. The T(2) results were similar, but less dramatic. The MT pseudo first-order exchange rate, RM(0B), did not depend on the contrast agent concentration, as expected, and was significantly faster for trypsinized and slower for IL-1beta-treated cartilage. In both cases, the MT fraction of the macromolecular pool M(0B) decreased while only trypsinized cartilage showed an increase in MT exchange rate R. The MT ratio (MTR) decreased with increasing Gd-DTPA(2-) concentration. However, interpretation of the MTR results in the presence of Gd-DTPA(2-) was complicated due to competing effects of increased longitudinal relaxivity and MT exchange. Therefore, in a cartilage sample with an unknown degree of GAG depletion and some collagen damage, a full MT analysis might be used to probe the molecular state of cartilage, but it would not be possible to use a simple MTR measurement after the administration of Gd-DTPA(2-) to differentially determine the amount of cartilage degradation in the sample.

Magnetization transfer in MRI: a review.

This review describes magnetization transfer (MT) contrast in magnetic resonance imaging. A qualitative description of how MT works is provided along with experimental evidence that leads to a quantitative model for MT in tissues. The implementation of MT saturation in imaging sequences and the interpretation of the MT-induced signal change in terms of exchange processes and direct effects are presented. Finally, highlights of clinical uses of MT are outlined and future directions for investigation proposed.

MR properties of rat sciatic nerve following trauma.

T(1) and T(2) relaxation times, magnetization transfer (MT), and diffusion anisotropy of rat sciatic nerve were measured at different time intervals following trauma. The nerve injury was induced by either cutting (irreversible nerve degeneration) or crushing (degeneration followed by regeneration). The MR properties were measured for proximal and distal portions of the injured nerve. The portions of the nerve proximal to the induced injury exhibited MR characteristics similar to those of normal nerves, whereas the distal portions showed significant differences in all MR parameters. These differences diminished in the regenerating nerves within approximately 4 weeks post injury. In the case of irreversible nerve damage, the differences in the distal nerves were slightly larger and did not resolve even 6 weeks after induced trauma. The MR measurements were correlated with histopathology exams. Observed changes in tissue microstructure, such as demyelination, inflammation, and axonal loss, can result in a significant increase in the average T(1) and T(2) relaxation times, reduction in the MT effect, and decrease in diffusion anisotropy. MR parameters, therefore, are very good indicators of nerve damage and may be useful in monitoring therapies that assist nerve regeneration. Magn Reson Med 45:415-420, 2001.

Gd-DTPA relaxivity depends on macromolecular content.

Gd-DTPA T(1) relaxivity of water protons was measured at 1.5 T and room temperature as a function of macromolecular content in model systems. Gd-DTPA relaxivity was found to increase with macromolecular concentration. The results of this study indicate that the Gd-DTPA relaxivity in tissue extracellular compartment could be as much as 30-70% higher than that of Gd-DTPA in saline. Quantitative MR analyses that use T(1) as an estimation of local Gd-DTPA concentration require a priori determination of the Gd relaxivity in tissue.

Analysis of changes in MR properties of tissues after heat treatment.

To characterize changes in the MR parameters of tissues due to thermal coagulation, a series of T(1), T(2), diffusion, and magnetization transfer measurements were performed on a variety of ex vivo tissues: murine slow twitch skeletal muscle, murine cardiac muscle, murine cerebral hemisphere, bovine white matter, murine liver tissue, bovine retroperitoneal adipose tissue, hen egg white, human prostate and human blood. Standardized heat treatments were performed for each tissue type, over the temperature range from 37 degrees C to 90 degrees C. For all tissues, changes in each MR measurement resulting from thermal coagulation were observed above a threshold temperature of approximately 60 degrees C. These changes are explained based on biophysical knowledge of thermal damage mechanisms and the MR properties of normal tissues, and are particularly relevant for interpreting the changes in image contrast that are observed when MRI is used to guide and monitor thermal coagulation therapy procedures. Magn Reson Med 42:1061-1071, 1999.

Characterizing white matter with magnetization transfer and T(2).

A magnetization-transfer (MT) CPMG hybrid experiment was performed to analyze T(2) relaxation and MT characteristics in bovine optic nerve. Two exchanging liquid pools with their own, independent MT characteristics were necessary to model both the T(2) relaxation and the MT data. The model agrees well with the experimental data and yields physically realistic parameters. The MT effect for myelin water is approximately nine time larger than that for intra/intercellular water, indicating that the MT characteristics observed for white matter are mainly related to myelin. The model can be used to probe parameters that would be difficult to achieve experimentally. The exchange process between the two tissue compartments does not drastically affect the amplitudes and relaxation rates of the T(2) components, but is fast enough to significantly influence their MT characteristics. Although, both the MT and T(2) experiments described in this paper are too time consuming to be applied in routine clinical work, presented results can be useful in interpreting clinical pulse sequences that are sensitive to myelin. Magn Reson Med 42:1128-1136, 1999.

Tracking oxygen effects on MR signal in blood and skeletal muscle during hyperoxia exposure.

Blood and muscle T1 and T2 relaxivity was examined under normoxic (air; 20.8% O2) and hyperoxic (100% O2) conditions to determine whether the oxygenation state of blood in the large vessels and in the microcirculation can be monitored in vivo. The femoral artery/vein and the soleus and gastrocnemius muscles were examined in healthy human male volunteers. Arterial blood T1 decreased with hyperoxia, while venous blood T2 increased, due to increased dissolved O2 and decreased deoxyhemoglobin, respectively. A biexponential T2 model of muscle is proposed, where the short T2 component reflects primarily the intracellular and interstitial compartments (in fast exchange), and the long T2 reflects blood. In this model, the long T2 component increased with hyperoxia exposure. This was more evident in slow twitch (soleus) than in fast twitch (gastrocnemius) muscle. It is concluded that changes in the long T2 component reflect change in the microcirculation oxygenation state.

Diffusional anisotropy of T2 components in bovine optic nerve.

A diffusion-CPMG hybrid experiment was used to analyze the diffusion characteristics of different T2 relaxation components in bovine optic nerve. Data were collected using a pulsed field gradient (PFG) multi spin echo (MSE) CPMG sequence for parallel and perpendicular axon orientation and four diffusion times. The apparent diffusion coefficient (ADC) was evaluated for two observed T2 components as a function of axonal orientation and diffusion time delta. The short T2 component exhibited minor diffusional anisotropy and larger ADC, whereas the long T2 component showed significant anisotropy effects. This is consistent with the hypothesis that the short T2 component is associated with water within the myelin sheath, which is less restricted than axonal water that is limited by cell membrane permeability.

Integrated analysis of diffusion and relaxation of water in blood.

Diffusion and T2 relaxation of water both inside and outside red blood cells (RBCs) in human blood were investigated using a hybrid NMR pulse sequence to obtain a more quantitative understanding of the diffusion and relaxation behavior of water in paramagnetic-doped blood samples. The data were analyzed by both examining the relaxation properties of the system after each diffusion weighting and looking at the diffusion properties at each echo time. The results illustrate how diffusion-sensitizing gradients affect the T2 spectra of blood and how relaxation weighting changes the curvature of the diffusion curves, thereby demonstrating the close coupling between diffusion and T2 relaxation. A three-pool model, consisting of RBCs, plasma, and macromolecular protons, was used to model the data from the diffusion-relaxation hybrid experiments. The model was found to describe all the characteristic features of the experimental data well and was used to evaluate the approximations involved in the conventional analysis methods and elucidate the nature of the relaxing and diffusing components. Compared with the separate diffusion and relaxation experiments, the diffusion-relaxation hybrid experiments are less time-consuming, result in better parameter determinations, and may be useful in analyzing diffusion-T2 coupling in tissues with more complicated multiexponential T2 behavior.

Water dynamics in human blood via combined measurements of T2 relaxation and diffusion in the presence of gadolinium.

An analytical model of tissue relaxation and restricted diffusion in human blood is presented. The blood tissue model is composed of three different compartments: red blood cells, plasma, and macromolecular protons. The relaxation rate constants and free diffusion coefficients of intracellular and extracellular water may differ. Analytical formulas for signal loss due to relaxation and diffusion in the Carr-Purcell Meiboom-Gill and pulsed-field-gradient multispin echo experiments for this tissue model are derived. The model is fitted to the experimental data for human blood with various concentrations of Gadolinium contrast agent. The obtained model parameters are realistic. The validity and sensitivity of the model are also discussed.

An analytical model of restricted diffusion in bovine optic nerve.

An analytical model of restricted diffusion in bovine optic nerve is presented. The nerve tissue model is composed of two different objects: prolate ellipsoids (axons) and spheres (glial cells) surrounded by partially permeable membranes. The free diffusion coefficients of intracellular and extracellular water may differ. Analytical formulas for signal loss due to diffusion in the pulsed gradient spin echo (PGSE) experiment for this tissue model are derived. The model is fitted to experimental data for bovine optic nerve. The obtained model parameters are shown to be reasonable. The model describes all of the characteristics of the PGSE data: anisotropy, upward curvature of decay curves, and diffusion time dependence. The validity and sensitivity of the model are also discussed.

Anisotropy of NMR properties of tissues.

Orientational anisotropy of T2 and T1 relaxation times, diffusion, and magnetization transfer has been investigated for six different tissues: tendon, cartilage, kidney, muscle, white matter, and optic nerve. Relaxation anisotropy was observed for tendon and cartilage, and diffusional anisotropy was measured in kidney, muscle, white matter, and optic nerve. All other NMR measurements of these tissues showed no orientational dependence. This pattern of NMR anisotropies can be interpreted from the underlying geometrical structures of the tissues.

Relaxivity and magnetization transfer of white matter lipids at MR imaging: importance of cerebrosides and pH.

PURPOSE: To measure the effect of the major lipid components of white matter on the relaxation times and magnetization transfer (MT) of water protons. MATERIALS AND METHODS: Multilamellar vesicle (MLV) suspensions of pure phosphatidylcholine (PC) and PC with varying proportions of cholesterol (CHOL), sphingomyelin (SPH), and galactocerebroside (GC) were produced at varying pH. T1, T2, and MT were measured. RESULTS: Suspensions consisting of PC with CHOL or SPH caused greater shortening of T1 and T2 and slightly greater MT effects than did PC alone. Suspensions consisting of GC and PC caused the greatest decrease in relaxation times, and the MT effect was two to three times greater than with either CHOL-PC or SPH-PC suspensions. At acidic pH, the relaxation time changes and the MT effects with CHOL-PC, SPH-PC, and GC-PC suspensions were greater than the effects of the same MLVs at physiologic pH. CONCLUSION: GC has the strongest effect on relaxivity and MT of all the major white matter lipids. The relaxivity and MT observed with white matter lipids is pH dependent, indicating that chemical exchange of protons likely contributes to relaxivity and MT.

Quantitative interpretation of magnetization transfer.

Magnetization transfer contrast (MTC) experiments using off-resonance irradiation have been performed with an agar gel model by systematically varying offset frequency, amplitude of the RF irradiation and gel concentration. The experimental results are shown to be quantitatively modelled by a two-pool system consisting of a liquid pool with a Lorentzian line shape and a small semisolid pool with a Gaussian lineshape. The fitted model yields physically realistic fundamental parameters with a T2 of the semisolid pool of 13 microseconds. Further analysis shows that the off-resonance irradiation MTC experiment had significant limitations in its ability to saturate the semisolid pool without directly affecting the liquid component.