A Review of Magnetic Particle Imaging and Perspectives on Neuroimaging.

Magnetic particle imaging is an emerging tomographic technique with the potential for simultaneous high-resolution, high-sensitivity, and real-time imaging. Magnetic particle imaging is based on the unique behavior of superparamagnetic iron oxide nanoparticles modeled by the Langevin theory, with the ability to track and quantify nanoparticle concentrations without tissue background noise. It is a promising new imaging technique for multiple applications, including vascular and perfusion imaging, oncology imaging, cell tracking, inflammation imaging, and trauma imaging. In particular, many neuroimaging applications may be enabled and enhanced with magnetic particle imaging. In this review, we will provide an overview of magnetic particle imaging principles and implementation, current applications, promising neuroimaging applications, and practical considerations.

Evaluation of PEG-coated iron oxide nanoparticles as blood pool tracers for preclinical magnetic particle imaging.

Superparamagnetic iron oxide (SPIO) nanoparticles with optimized and well-characterized properties are critical for Magnetic Particle Imaging (MPI). MPI is a novel in vivo imaging modality that promises to integrate the speed of X-ray CT, safety of MRI and sensitivity of PET. Since SPIOs are the source of MPI signal, both the core and surface properties must be optimized to enable efficient in vivo imaging with pharmacokinetics tailored for specific imaging applications. Existing SPIOs like Resovist (ferucarbotran) provide a suboptimal MPI signal, and further limit MPI's in vivo utility due to rapid systemic clearance. An SPIO agent with a long blood half-life (t1/2) would be a versatile MPI tracer with widespread applications. Here we show that a long circulating polyethylene glycol (PEG)-coated SPIO tracer, LS-008, provides excellent colloidal stability and a persistent intravascular MPI signal, showing its potential as the first blood pool tracer optimized for MPI. We evaluated variations of PEG coating and found that colloidal stability of tracers improved with the increasing PEG molecular weight (keeping PEG loading constant). Blood circulation in mice, evaluated using Magnetic Particle Spectrometry (MPS), showed that the t1/2 of SPIO tracers varied with both PEG molecular weight and loading. LS-008, coated with 20 kDa PEG at 18.8% loading capacity, provided the most promising long-term colloidal stability with a t1/2 of about 105 minutes in mice. In vivo MPI imaging with LS-008 using a 7 T/m/µ0 3D x-space MPI mouse scanner revealed a prolonged intravascular signal (3-5 hours) post-injection. Our results show the optimized magnetic properties and long systemic retention of LS-008 making it a promising blood pool MPI tracer, with potential to enable MPI imaging in cardio- and cerebrovascular disease models, and solid tumor quantification and imaging via enhanced permeation and retention.

Finite magnetic relaxation in x-space magnetic particle imaging: Comparison of measurements and ferrohydrodynamic models.

Magnetic Particle Imaging (MPI) is an emerging tomographic imaging technology that detects magnetic nanoparticle tracers by exploiting their non-linear magnetization properties. In order to predict the behavior of nanoparticles in an imager, it is possible to use a non-imaging MPI relaxometer or spectrometer to characterize the behavior of nanoparticles in a controlled setting. In this paper we explore the use of ferrohydrodynamic magnetization equations for predicting the response of particles in an MPI relaxometer. These include a magnetization equation developed by Shliomis (Sh) which has a constant relaxation time and a magnetization equation which uses a field-dependent relaxation time developed by Martsenyuk, Raikher and Shliomis (MRSh). We compare the predictions from these models with measurements and with the predictions based on the Langevin function that assumes instantaneous magnetization response of the nanoparticles. The results show good qualitative and quantitative agreement between the ferrohydrodynamic models and the measurements without the use of fitting parameters and provide further evidence of the potential of ferrohydrodynamic modeling in MPI.

Eddy current-shielded x-space relaxometer for sensitive magnetic nanoparticle characterization.

The development of magnetic particle imaging (MPI) has created a need for optimized magnetic nanoparticles. Magnetic particle relaxometry is an excellent tool for characterizing potential tracers for MPI. In this paper, we describe the design and construction of a high-throughput tabletop relaxometer that is able to make sensitive measurements of MPI tracers without the need for a dedicated shield room.

Noise performance of a precision pulsed electromagnet power supply for magnetic resonance imaging.

Prepolarized magnetic resonance imaging (PMRI) uses two pulsed electromagnets to achieve high-field image quality with the benefits of low-field data acquisition. The principal challenge with all resistive MRI systems is the implementation of a highly precise magnet current supply. The noise current through the magnet is fundamentally limited by the current transducer used to provide feedback and the voltage reference used to generate the demand signal. Field instability in the main field magnet can both corrupt the received data and degrade the robustness of Carr¿Purcell¿Meiboom¿Gill (CPMG) echo trains, which are paramount to efficient imaging in PMRI. In this work, we present the magnet control system that achieved sufficient field stability for PMRI at $0.5/0.13$ T, identify the dominant sources of noise in the control system, examine the imaging artifacts that can occur if the field stability is insufficient, and identify how the design can be improved for better field stability, should it be required for future implementations of PMRI.

Identification of ENV determinants in V3 that influence the molecular anatomy of CCR5 utilization.

The V3 loop of the ENV glycoprotein exerts a dominant influence on the interaction of gp120 with coreceptors. Primary env genes cloned from sequential isolates from two seroconverters revealed Pro-->Ala conversion in the conserved GPG motif of the V3 crown in seven of 17 R5 ENV. ENV containing the GPG motif in the V3 crown had fusogenic activity with chimeric receptors containing either the N terminus or loops of CCR5, whereas those with the GAG variant utilized only the former. Site-directed mutagenesis of multiple primary and prototypic R5 env genes demonstrated that the GPG motif was necessary for dual utilization of the N terminus and body of CCR5 in both gain and loss-of-function experiments. All ENV containing the GPG V3 crown showed CCR5 binding in the presence of soluble CD4, whereas it was not detected with the GAG variants. Molecular dynamic simulations of a V3 peptide predicts that the Pro-->Ala substitution results in a conformational change with loss of the crown structure. These studies demonstrate that sequences in the third hypervariable region determine the specificity of coreceptor utilization for fusion, and that a conserved motif in the crown directly influences the molecular anatomy of the interaction between gp120 and CCR5.

MR imaging of articular cartilage using driven equilibrium.

The high incidence of osteoarthritis and the recent advent of several new surgical and non-surgical treatment approaches have motivated the development of quantitative techniques to assess cartilage loss. Although magnetic resonance (MR) imaging is the most accurate non-invasive diagnostic modality for evaluating articular cartilage, improvements in spatial resolution, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) would be valuable. Cartilage presents an imaging challenge due to its short T(2) relaxation time and its low water content compared with surrounding materials. Current methods sacrifice cartilage signal brightness for contrast between cartilage and surrounding tissue such as bone, bone marrow, and joint fluid. A new technique for imaging articular cartilage uses driven equilibrium Fourier transform (DEFT), a method of enhancing signal strength without waiting for full T(1) recovery. Compared with other methods, DEFT imaging provides a good combination of bright cartilage and high contrast between cartilage and surrounding tissue. Both theoretical predictions and images show that DEFT is a valuable method for imaging articular cartilage when compared with spoiled gradient-recalled acquisition in the steady state (SPGR) or fast spin echo (FSE). The cartilage SNR for DEFT is as high as that of either FSE or SPGR, while the cartilage-synovial fluid CNR of DEFT is as much as four times greater than that of FSE or SPGR. Implemented as a three-dimensional sequence, DEFT can achieve coverage comparable to that of other sequences in a similar scan time. Magn Reson Med 42:695-703, 1999.

Resistive homogeneous MRI magnet design by matrix subset selection.

A new technique for designing resistive homogeneous multicoil magnets for magnetic resonance imaging (MRI) is presented. A linearly independent subset of coils is chosen from a user-defined feasible set using an efficient numerical algorithm. The coil currents are calculated using a linear least squares algorithm to minimize the deviation of the actual magnetic field from the target field. The solutions are converted to practical coils by rounding the currents to integer ratios, selecting the wire gauge, and optimizing the coil cross-sections. To illustrate the technique, a new design of a short, homogeneous MRI magnet suitable for low-field human torso imaging is presented. Magnets that satisfy other constraints on access and field uniformity can also be designed. Compared with conventional techniques that employ harmonic expansions, this technique is flexible, simple to implement, and numerically efficient.

Background suppression with multiple inversion recovery nulling: applications to projective angiography.

We have developed a technique to accurately null the longitudinal magnetization (Mz) of background material. This suppression involves first saturating the longitudinal magnetization (Mz) of a region, and then applying several nonselective inversions. The inversions are timed relative to the saturation such that Mz is nulled across a broad range of T1 at a predetermined time after the initial saturation. B1 and B0 inhomogeneity, which could lead to inaccurate suppression, are dealt with by the combination of a multiple tip saturation sequence and four adiabatic inversion pulses. The suppression sequence can be used to form projective angiograms by selectively tagging the imaging region with the saturation pulse. After the inversions are played out, a projection taken through the tag region when Mz is nulled will only contain signal from blood that has flown into the region after the saturation. Since only two dimensions are acquired, the technique can acquire gated projection angiograms in reasonable scan times. Representative inflow MIR angiograms of the carotid arteries and renal arteries show excellent background suppression.

A readout magnet for prepolarized MRI.

Conventional MRI systems rely on large magnets to generate a field that is both strong and extremely uniform. This field is usually produced by a heavy permanent magnet or a cryogenically cooled superconductor. An alternative approach, called prepolarized MRI (PMRI), employs two separate fields produced by two different magnets. A strong and inhomogeneous magnetic field is used to polarize the sample. After polarization, a weak magnetic field is used for readout. These fields can be produced by two separate resistive electromagnets that cost significantly less than a single permanent or superconducting magnet. At Stanford, the authors are constructing a PMRI prototype scanner suitable for imaging human extremities roughly 20 cm in diameter. With this system the authors hope to demonstrate comparable image quality to MRI with reduced system cost. The authors' initial work on low-frequency reception indicates that it will be possible to obtain comparable image signal-to-noise ratio to an MRI scanner operating at the same polarizing field strength. To reduce the capital cost of the system, the authors use resistive electromagnets. Here the authors discuss the full development of the readout magnet including important design considerations, shimming, and field plots. These encouraging results are an important step toward evaluating the cost effectiveness of PMRI.

Novel approaches to low-cost MRI.

This paper presents a combination of speculative approaches, some related to earlier work and some apparently novel, which show great promise in providing a new class of MRI machines that would be considerably less expensive. This class would have advantages and disadvantages as compared to existing MRI, over and above that of low cost. The disadvantages include the apparent inability to perform classic spectroscopy, and limited flexibility in the area of selective excitation. The advantages include a fundamental immunity to inhomogeneity and susceptibility problems, the ability to create a wide class of machines that are designed for specific anatomy-related applications, the ability to design open machines for physician access, and improved capability for high speed imaging. Generic to all of the methods presented are a pulsed polarizing field and an oscillatory read-out bias field. The pulsed field initially polarizes the magnetic moments. Since it is not on during the readout operation it has negligible homogeneity requirements since changes in the field amplitude will merely shade the image intensity. During readout a relatively low bias field is used. To enable the use of a relatively inhomogeneous bias field, an oscillatory field is used that has a zero average value. This prevents any long-term buildup of phase errors due to a frequency error associated with inhomogeneity. Thus the average bias frequency will be determined solely by the frequency rather than the amplitude of the bias field. Three methods are described, all including the above features. The first two involve imaging in the laboratory frame, while the third involves imaging in the rotating frame. The second approach requires no RF excitation and the third approach uses RF bias and gradient signals. Some approaches to slice selection are described.

Pulsed saturation transfer contrast.

In vivo 1H conventional NMR image contrast generation usually relies on the macroscopic T1 and T2 relaxation parameters of the tissues of interest. Recently cross-relaxation related image contrast has been reported by Wolff and Balaban in animal models. Due primarily to the broad lineshape of the intended saturation spin pool and the use of off-resonance irradiation, high specific absorption rate and an auxiliary RF amplifier have been necessary to produce these images. The relatively long spin-lattice relaxation property of this spin pool, however, suggests the use of pulse methods to achieve saturation. In this paper, we show that short-T2 spin pools can be selectively saturated with short intense RF pulses. Cross-relaxation time constants can be measured using the technique of saturation recovery. In vivo magnetization-transfer-weighted images can be produced using pulses on commercial whole-body imagers without additional hardware.

Two-dimensional selective adiabatic pulses.

Using the technique of separable k-space excitation, we have designed a two-dimensional selective adiabatic pulse that inverts magnetization from a square region in the xy plane with insensitivity to RF variations. We also have designed a two-dimensional adiabatic pulse that inverts selectively in frequency and in one spatial dimension. The pulses should be useful for both MR imaging and spectroscopy. We present experimental results to demonstrate that the two-dimensional adiabatic pulses are feasible on commercial MR imaging systems.

A reduced power selective adiabatic spin-echo pulse sequence.

We introduce a selective adiabatic pulse sequence suitable for generating selective spin-echoes for both MR imaging and spectroscopy. The technique is simple; one uses the echo generated by any pair of identical selective adiabatic inversion pulses. The nonlinear phase across the slice is compensated perfectly by the second pi pulse. This compensation is immune to RF inhomogeneity and nonlinearity. For imaging applications, we concentrate on a reduced-power version of the pulse sequence in which time is traded off variably for RF amplitude in the presence of a time-varying gradient. This technique, known as variable-rate excitation, mildly degrades the off-resonant slice profile when applied to amplitude-modulated pulses. We present theoretical explanations and experimental results that show that the variable-rate adiabatic pulses are immune to off-resonant degradation of the magnitude normally encountered in MR imaging.

MR angiography by selective inversion recovery.

A modified inversion-recovery sequence is introduced which performs subtraction angiography by varying time-of-flight effects of blood flowing into an imaged slab. The selective 180 degrees excitation inverts different regions between measurements to isolate arterial and/or venous blood. On normal human subjects, high-resolution carotid artery angiograms have been obtained.

Optimal control solutions to the magnetic resonance selective excitation problem.

Most magnetic resonance imaging sequences employ field gradients and amplitude modulated RF pulses to excite only those spins lying in a specific plane. The fidelity of the resulting magnetization distribution is crucial to overall image resolution. Conventional RF-pulse design techniques rely on the small tip-angle approximation to Bloch's equation, which is inadequate for the design of 90 degrees and 180 degrees pulses. This paper demonstrates the existence of a selective pulse, and provides a sound mathematical and computational basis for pulse design. It is shown that the pulses are optimal in the class of piecewise continuous functions of duration T. An optimal pulse is defined as the pulse on the interval that achieves a magnetization profile "closest" to the desired distribution. Optimal control theory provides the mathematical basis for the new pulse design technique. Computer simulations have verified the efficacy of the 90 degrees and the 180 degrees inversion and "pancake-flip" optimal pulses.