Open-source magnetic resonance imaging: Improving access, science, and education through global collaboration.

Open-source practices and resources in magnetic resonance imaging (MRI) have increased substantially in recent years. This trend started with software and data being published open-source and, more recently, open-source hardware designs have become increasingly available. These developments towards a culture of sharing and establishing nonexclusive global collaborations have already improved the reproducibility and reusability of code and designs, while providing a more inclusive approach, especially for low-income settings. Community-driven standardization and documentation efforts are further strengthening and expanding these milestones. The future of open-source MRI is bright and we have just started to discover its full collaborative potential. In this review we will give an overview of open-source software and open-source hardware projects in human MRI research.

Joint multi-field T1 quantification for fast field-cycling MRI.

PURPOSE: Recent developments in hardware design enable the use of fast field-cycling (FFC) techniques in MRI to exploit the different relaxation rates at very low field strength, achieving novel contrast. The method opens new avenues for in vivo characterizations of pathologies but at the expense of longer acquisition times. To mitigate this, we propose a model-based reconstruction method that fully exploits the high information redundancy offered by FFC methods. METHODS: The proposed model-based approach uses joint spatial information from all fields by means of a Frobenius - total generalized variation regularization. The algorithm was tested on brain stroke images, both simulated and acquired from FFC patients scans using an FFC spin echo sequences. The results are compared to three non-linear least squares fits with progressively increasing complexity. RESULTS: The proposed method shows excellent abilities to remove noise while maintaining sharp image features with large signal-to-noise ratio gains at low-field images, clearly outperforming the reference approach. Especially patient data show huge improvements in visual appearance over all fields. CONCLUSION: The proposed reconstruction technique largely improves FFC image quality, further pushing this new technology toward clinical standards.

A Novel Class of 1 H-MRI Contrast Agents Based on the Relaxation Enhancement Induced on Water Protons by 14 N-Containing Imidazole Moieties.

This study reports the development of a completely new class of MRI contrast agents, displaying remarkable relaxation effects in the absence of paramagnetic metal ions. Their detection requires the acquisition of images at variable magnetic field strength as provided by fast field cycling imaging scanners. They contain poly-histidine chains (poly-His), whose imidazole groups generate 14 N-quadrupolar-peaks that cause a relaxation enhancement of water protons at a frequency (1.38±0.3 MHz) that is readily detectable from the frequencies associated with endogenous proteins. The poly-His quadrupolar peaks are detectable only when the polymer is in a solid-like form, that is, at pH>6.6. Above this value, their intensity is pH dependent and can be used to report on the occurring pH changes. On this basis, the poly-His moieties were conjugated to biocompatible polymers, such as polylactic and glycolic acid, in order to form stable nanoparticles able to encapsulate structured water in their core. FFC images were acquired to assess their contrast-generating ability.

Mechanism of Water Dynamics in Hyaluronic Dermal Fillers Revealed by Nuclear Magnetic Resonance Relaxometry.

1 H spin-lattice nuclear magnetic resonance relaxation experiments were performed for five kinds of dermal fillers based on hyaluronic acid. The relaxation data were collected over a broad frequency range between 4 kHz and 40 MHz, at body temperature. Thanks to the frequency range encompassing four orders of magnitude, the dynamics of water confined in the polymeric matrix was revealed. It is demonstrated that translation diffusion of the confined water molecules exhibits a two-dimensional character and the diffusion process is slower than diffusion in bulk water by 3-4 orders of magnitude. As far as rotational dynamics of the confined water is concerned, it is shown that in all cases there is a water pool characterized by a rotational correlation time of about 4×10-9  s. In some of the dermal fillers a fraction of the confined water (about 10 %) forms a pool that exhibits considerably slower (by an order of magnitude) rotational dynamics. In addition, the water binding capacity of the dermal fillers was quantitatively compared.

Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy.

Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of l-arginine into l-citrulline. NO is a free radical gas with a short half-life in vivo (≈5s), therefore direct NO quantification is challenging. An indirect method - based on quantifying conversion of an l-Arg- to l-Cit-derivative by 1H NMR spectroscopy - is herein proposed. A small library of pyridyl containing l-Arg derivatives was designed and synthesised. In vitro tests showed that compounds 4a-j and 11a-c were better or equivalent substrates for the eNOS enzyme (NO2- production=19-46µM) than native l-Arg (NO2- production=25µM). Enzymatic conversion of l-Arg to l-Cit derivatives could be monitored by 1H NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo.

Rapid field-cycling MRI using fast spin-echo.

PURPOSE: Fast field-cycling MRI (FFC-MRI) is a technique that promises to expand upon the diagnostic capabilities of conventional MRI by allowing the main field, B0 , to be varied during a pulse sequence, thus allowing access to new types of endogenous contrast. However, this necessitates longer scan times, which can limit the technique's application to clinical research. In this paper, an adaptation of the fast spin-echo (FSE) pulse sequence for use with FFC-MRI is presented, known as field-cycling fast spin-echo (FC-FSE). This technique allows much faster image acquisition, thus shortening scan times significantly. METHODS: Image quality and relaxometric accuracy were assessed by comparison of phantom images with data obtained using conventional techniques. As proof of principle, relaxometric images were obtained from the thighs of a human volunteer. RESULTS: Image quality remains good for speedup factors of up to 4-fold. The accuracy of relaxometry data is in good agreement with conventional techniques. Results from a volunteer study were encouraging, demonstrating that the technique is sensitive enough to detect quadrupole peaks in vivo. CONCLUSION: The technique has been demonstrated in phantom experiments with little loss of image quality or relaxometric accuracy. Initial in-vivo results pave the way for future clinical studies.

A flexible 8.5 MHz litz wire receive array for field-cycling imaging.

Objectives. Low frequency coils present unique challenges as loop losses, component losses, and the supporting electronics can significantly degrade the signal-to-noise ratio (SNR). SNR may already be a limiting factor with MRI at low field (and frequency), therefore the minimization of additional loss is particularly important. If interactions between loops are managed, array coils can provide increased SNR, coverage, and potentially imaging speed. In this work, we investigate methods to characterise and preserve SNR from a low frequency coil array, allowing a more geometrically conforming array for quick, no-tune application with various anatomies.Approach. Single and multi-turn, 16.2 cm diameter litz wire loops were constructed and characterised for losses under various loading conditions. Low noise preamplifiers were acquired and characterized, as well as interfacing electronics were developed and evaluated. A bench level SNR test was implemented to observe the effects of tuning and loading on individual coils. The results were used to select a design for construction of a 6-channel, flex array coil.Main results. Ultra fine strand litz wire exhibited lower losses than equivalent diameter solid wire which should translate to improved SNR and provides the mechanical flexibility needed in a conforming array. Single turn loop losses were dominant under all loading conditions; however, 2 and 3 turn loops were body loss dominated under modest loading conditions. Preamplifier blocking achieved was well short of our design goal and critical overlaps became necessary for coil-to-coil interaction control. Our finished array, a 3-channel posterior array coil and a 3-channel anterior array coil, conforms nicely to various anatomies and is providing consistent results in various volunteer study trials.Significance. Receive coils are challenging at low fields as loop losses often limit the final SNR. This is exacerbated in an array coil as loops may be smaller and not coupled well to the body. In this work we have demonstrated that body loss dominance is possible with 16.2 cm loops at 8.5 MHz. We have optimized, built, and tested low noise interfacing electronics and characterized the SNR penalties as the tuning and loading is varied, a key parameter in a geometrically flexible array designed for rapid setup. The resultant 6-channel, general-purpose array is supporting various Field-Cycling Imaging studies where body habitus and anatomies require a flexible, adaptable array coil which can be quickly positioned and utilized.

Detection of osteoarthritis in knee and hip joints by fast field-cycling NMR.

It is known that in the early stages of osteoarthritis, the concentration of glycan proteins decreases in articular cartilage. This phenomenon is under active research to develop a means to characterize osteoarthritis accurately in the early stages of the disease, when still reversible. However, no method of quantification has yet shown clear success in this area. In this article, we propose a novel approach to detect glycan depletion using fast field-cycling NMR. This technique was previously reported to allow noninvasive measurement of protein concentration via the (14)N quadrupolar relaxation in certain amide groups. We have demonstrated that the articular cartilage exhibits clear quadrupolar peaks that can be measured by a benchtop fast field-cycling NMR device and which changes significantly between normal and diseased tissues (P < 0.01). This signal is probably glycan specific. The method may have potential for early evaluation of osteoarthritis in patients on fast field-cycling-MRI scanners currently under evaluation in the authors' laboratory.

Measurement of fibrin concentration by fast field-cycling NMR.

The relaxation of (1)H nuclei due to their interaction with quadrupolar (14)N nuclei in gel structures is measured using fast field-cycling NMR. This phenomenon called quadrupolar dips has been reported in different (1)H-(14)N bond-rich species. In this study, we have studied quadrupolar dips in fibrin, an insoluble protein that is the core matrix of thrombi. Fibrin was formed by the addition of thrombin to fibrinogen in 0.2% agarose gel. T(1)-dispersion curves were measured using fast field-cycling NMR relaxometry, over the field range of 1.5-3.5 MHz (proton Larmor frequency), and were analyzed using a curve-fitting algorithm. A linear increase of signal amplitude with increasing fibrin concentration was observed. This agrees with the current theory that predicts a linear relationship of signal amplitude with the concentration of contributing (14)N spins in the sample. Interestingly, fibrin formation gave rise to the signal, regardless of crosslinking induced by the transglutaminase factor XIIIa. To investigate the effect of proteins that might be trapped in the thrombi in vivo, the plasma protein albumin was added to the fibrin gel, and an increase in the quadrupolar signal amplitude was observed. This study can potentially be useful for thrombi classification by fast field-cycling MRI techniques.

Role of Transmembrane Water Exchange in Glioma Invasion/Migration: In Vivo Preclinical Study by Relaxometry at Very Low Magnetic Field.

This work shows that the longitudinal relaxation differences observed at very low magnetic fields between invasion/migration and proliferation processes on glioma mouse models in vivo are related to differences in the transmembrane water exchange basically linked to the aquaporin expression changes. Three glioma mouse models were used: Glio6 and Glio96 as invasion/migration models and U87 as cell proliferation model. In vivo proton longitudinal relaxation-rate constants (R1) at very low fields were measured by fast field cycling NMR (FFC-NMR). The tumor contribution to the observed proton relaxation rate, R1tum (U87: 12.26 ± 0.64 s−1; Glio6: 3.76 ± 0.88 s−1; Glio96: 6.90 ± 0.64 s−1 at 0.01 MHz), and the intracellular water lifetime, τin (U87: 826 ± 19 ms; Glio6: 516 ± 8 ms; Glio96: 596 ± 15 ms), were found to be good diagnostic hallmarks to distinguish invasion/migration from proliferation (p < 0.01 and 0.001). Overexpression of AQP4 and AQP1 were assessed in invasion/migration models, highlighting the pathophysiological role of these two aquaporins in water exchange that, in turn, determine the lower values in the observed R1 relaxation rate constant in glioma invasion/migration. Overall, our findings demonstrate that τin and R1 (measured at very low fields) are relevant biomarkers, discriminating invasion/migration from proliferation in vivo. These results highlight the use of FFC-NMR and FFC-imaging to assess the efficiency of drugs that could modulate aquaporin functions.

Rapid, automated measurement of dielectrophoretic forces using DEP-activated microwells.

Dielectrophoresis (DEP) is a physical effect that generates a force on polarisable particles experiencing a non-homogeneous electric field; studying the effect as a function of frequency allows the determination of the electrical properties of that particle, i.e., the electrical permittivity and conductivity. In the past, DEP-based techniques applied to the measurement of one or several cells at a time have been subject to many sources of noise, which result in an ambiguous or inaccurate result. However, improvements are possible by generating more information from the experiments. In this paper, we present a rapid automated system that measures the DEP spectrum from a large population of cells with a low level of noise using the microwell electrodes, based on a method of analysis that provides additional information about the electrical properties of the cells and a new theoretical approach was developed to obtain accurate, bias-free results in <5 min.

An Algorithm for Tracking the Position and Velocity of Multiple Neuronal Signals Using Implantable Microelectrodes In Vivo.

Increasingly complex multi-electrode arrays for the study of neurons both in vitro and in vivo have been developed with the aim of tracking the conduction of neural action potentials across a complex interconnected network. This is usually performed through the use of electrodes to record from single or small groups of microelectrodes, and using only one electrode to monitor an action potential at any given time. More complex high-density electrode structures (with thousands of electrodes or more) capable of tracking action potential propagation have been developed but are not widely available. We have developed an algorithm taking data from clusters of electrodes positioned such that action potentials are detected by multiple sites, and using this to detect the location and velocity of action potentials from multiple neurons. The system has been tested by analyzing recordings from probes implanted into the locust nervous system, where recorded positions and velocities correlate well with the known physical form of the nerve.

A new method for investigating osteoarthritis using Fast Field-Cycling nuclear magnetic resonance.

Osteoarthritis in synovial joints remains a major cause of long-term disability worldwide, with symptoms produced by the progressive deterioration of the articular cartilage. The earliest cartilage changes are thought to be alteration in its main protein components, namely proteoglycan and collagen. Loss of proteoglycans bound in the collagen matrix which maintain hydration and stiffness of the structure is followed by collagen degradation and loss. The development of new treatments for early osteoarthritis is limited by the lack of accurate biomarkers to assess the loss of proteoglycan. One potential biomarker is magnetic resonance imaging (MRI). We present the results of a novel MRI methodology, Fast Field-Cycling (FFC), to assess changes in critical proteins by demonstrating clear quantifiable differences in signal from normal and osteoarthritic human cartilage for in vitro measurements. We further tested proteoglycan extracted cartilage and the key components individually. Three clear signals were identified, two of which are related predominantly to the collagen component of cartilage and the third, a unique very short-lived signal, is directly related to proteoglycan content; we have not seen this in any other tissue type. In addition, we present the first volunteer human scan from our whole-body FFC scanner where articular cartilage measurements are in keeping with those we have shown in tissue samples. This new clinical imaging modality offers the prospect of non-invasive monitoring of human cartilage in vivo and hence the assessment of potential treatments for osteoarthritis. Keywords: Fast Field-Cycling NMR; human hyaline cartilage; Osteoarthritis; T1 dispersion; quadrupolar peaks; protein interactions.

Low-Field NMR Relaxometry for Intraoperative Tumour Margin Assessment in Breast-Conserving Surgery.

As conserving surgery is routinely applied for the treatment of early-stage breast cancer, the need for new technology to improve intraoperative margin assessment has become increasingly important. In this study, the potential of fast field-cycling 1H-NMR relaxometry as a new diagnostic tool was evaluated. The technique allows the determination of the tissue proton relaxation rates (R1), as a function of the applied magnetic field, which are affected by the changes in the composition of the mammary gland tissue occurring during the development of neoplasia. The study involved 104 small tissue samples obtained from surgical specimens destined for histopathology. It was found that a good accuracy in margin assessment, i.e., a sensitivity of 92% and a specificity of 85%, can be achieved by using two quantifiers, namely (i) the slope of the line joining the R1 values measured at 0.02 and 1 MHz and (ii) the sum of the R1 values measured at 0.39 and 1 MHz. The method is fast, and it does not rely on the expertise of a pathologist or cytologist. The obtained results suggest that a simplified, low-cost, automated instrument might compete well with the currently available tools in margin assessment.

Monitoring tissue implants by field-cycling 1H-MRI via the detection of changes in the 14N-quadrupolar-peak from imidazole moieties incorporated in a "smart" scaffold material.

This study is focused on the development of innovative sensors to non-invasively monitor the tissue implant status by Fast-Field-Cycling Magnetic Resonance Imaging (FFC-MRI). These sensors are based on oligo-histidine moieties that are conjugated to PLGA polymers representing the structural matrix for cells hosting scaffolds. The presence of 14N atoms of histidine causes a quadrupolar relaxation enhancement (also called Quadrupolar Peak, QP) at 1.39 MHz. This QP falls at a frequency well distinct from the QPs generated by endogenous semisolid proteins. The relaxation enhancement is pH dependent in the range 6.5-7.5, thus it acts as a reporter of the scaffold integrity as it progressively degrades upon lowering the microenvironmental pH. The ability of this new sensors to generate contrast in an image obtained at 1.39 MHz on a FFC-MRI scanner is assessed. A good biocompatibility of the histidine-containing scaffolds is observed after its surgical implantation in healthy mice. Over time the scaffold is colonized by endogenous fibroblasts and this process is accompanied by a progressive decrease of the intensity of the relaxation peak. In respect to the clinically used contrast agents this material has the advantage of generating contrast without the use of potentially toxic paramagnetic metal ions.

Towards applying NMR relaxometry as a diagnostic tool for bone and soft tissue sarcomas: a pilot study.

This work explores what Fast Field-Cycling Nuclear Magnetic Resonance (FFC-NMR) relaxometry brings for the study of sarcoma to guide future in vivo analyses of patients. We present the results of an ex vivo pilot study involving 10 cases of biopsy-proven sarcoma and we propose a quantitative method to analyse 1H NMR relaxation dispersion profiles based on a model-free approach describing the main dynamical processes in the tissues and assessing the amplitude of the Quadrupole Relaxation Enhancement effects due to 14N. This approach showed five distinct groups of dispersion profiles indicating five discrete categories of sarcoma, with differences attributable to microstructure and rigidity. Data from tissues surrounding sarcomas indicated very significant variations with the proximity to tumour, which may be attributed to varying water content but also to tissue remodelling processes due to the sarcoma. This pilot study illustrates the potential of FFC relaxometry for the detection and characterisation of sarcoma.

1H spin-lattice NMR relaxation in the presence of residual dipolar interactions - Dipolar relaxation enhancement.

A model of spin-lattice relaxation for spin-1/2 nuclei in the presence of a residual dipole-dipole coupling has been presented. For slow dynamics the model predicts a bi-exponential relaxation at low frequencies, when the residual dipole-dipole interaction dominates the Zeeman coupling. Moreover, according to the model a frequency-specific relaxation enhancement, referred to as Dipolar Relaxation Enhancement (DRE) in analogy to the Quadrupole Relaxation Enhancement (QRE) is expected. The frequency position of the relaxation maximum is determined by the amplitude of the residual dipole-dipole interaction. Experimental examples of relaxation properties that might be attributed to the DRE are presented. The DRE effect has the potential to be exploited, in analogy to QRE, as a unique source of information about molecular dynamics and structure.

Slow dynamics of solid proteins - Nuclear magnetic resonance relaxometry versus dielectric spectroscopy.

1H Nuclear Magnetic Resonance (NMR) relaxometry and Dielectric Spectroscopy (DS) have been exploited to investigate the dynamics of solid proteins. The experiments have been carried out in the frequency range of about 10 kHz-40 MHz for NMR relaxometry and 10-2Hz-20 MHz for DS. The data sets have been analyzed in terms of theoretical models allowing for a comparison of the correlation times revealed by NMR relaxometry and DS. The 1H spin-lattice relaxation profiles have been decomposed into relaxation contributions associated with 1H-1H and 1H-14N dipole - dipole interactions. The 1H-1H relaxation contribution has been interpreted in terms of three dynamical processes of time scales of 10-6s, 10-7s and 10-8s. It has turned out that the correlation times do not differ much among proteins and they are only weakly dependent on temperature. The analysis of DS relaxation spectra has also revealed three motional processes characterized by correlation times that considerably depend on temperature in contrast to those obtained from the 1H relaxation. This finding suggest that for solid proteins there is a contribution to the 1H spin-lattice relaxation associated with a kind of motion that is not probed in DS as it does not lead to a reorientation of the electric dipole moment.

In vivo assessment of tumour associated macrophages in murine melanoma obtained by low-field relaxometry in the presence of iron oxide particles.

Tumour-associated macrophages (TAM) are forced by cancer cells to adopt an anti-inflammatory phenotype and secrete factors to promote tumour invasion thus being responsible for poor patient outcome. The aim of this study is to develop a clinically applicable, non-invasive method to obtain a quantitative TAM detection in tumour tissue. The method is based on longitudinal proton relaxation rate (R1) measurements at low field (0.01-1 MHz) to assess the localization of ferumoxytol (clinical approved iron oxide particles) in TAM present in melanoma tumours, where R1 = 1/T1. R1 at low magnetic fields appears highly dependent on the intra or extra cellular localization of the nanoparticles thus allowing an unambiguous TAM quantification. R1 profiles were acquired on a Fast Field-Cycling relaxometer equipped with a 40 mm wide bore magnet and an 11 mm solenoid detection coil placed around the anatomical region of interest. The R1 values measured 3 h and 24 h after the injection were significantly different. At 24 h R1 exhibited a behavior similar to "in vitro" ferumoxytol-labelled J774A.1 macrophages whereas at 3 h, when the ferumoxytol distribution was extracellular, R1 exhibited higher values similar to that of free ferumoxytol in solution. This finding clearly indicated the intracellular localization of ferumoxytol at 24 h, as confirmed by histological analysis (Pearls and CD68 assays). This information could be hardly achievable from measurements at a single magnetic field and opens new horizons for cell tracking applications using FFC-MRI.