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Highlights • Fast Field-Cycling can assess proteoglycan content in vitro. • The T1 vs field strength profile of cartilage varies in osteoarthritis. • These biomarkers can potentially be accessed in vivo using Field-Cycling Imaging. • Potential application in clinical trials of new treatments for early osteoarthritis., 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

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.

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.

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.

1H 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., Mechanism of water diffusion: Profiting from the potential of NMR relaxometry to reveal mechanism of molecular motion in condensed matter, we demonstrate the 2D character of the translation diffusion of water in hyaluronic acid gels. The diffusion process is slower than diffusion in bulk water by 3–4 orders of magnitude.

Fast Field-Cycling (FFC) is a well-established Nuclear Magnetic Resonance (NMR) technique that exploits varying magnetic fields to quantify molecular motion over a wide range of time scales, providing rich structural information from nanometres to micrometres, non-invasively. Previous work demonstrated great potential for FFC-NMR biomarkers in medical applications; our research group has now ported this technology to medical imaging by designing a whole-body FFC Magnetic Resonance Imaging (FFC-MRI) scanner capable of performing accurate measurements non-invasively over the entire body, using signals from water and fat protons. This is a unique tool to explore new biomarkers related to disease-induced tissue remodelling. Our approach required making radical changes in the design, construction and control of MRI hardware so that the magnetic field is switched within 12.5 ms to reach any field strength from 50 μT to 0.2 T, providing clinically useful images within minutes. Pilot studies demonstrated endogenous field-dependant contrast in biological tissues in good agreement with reference data from other imaging modalities, confirming that our system can perform multiscale structural imaging of biological tissues, from nanometres to micrometres. It is now possible to confirm ex vivo results obtained from previous clinical studies, offering applications in diagnosis, staging and monitoring treatment for cancer, stroke, osteoarthritis and oedema.

A Special Issue of Physica Medica – European Journal of Medical Physics, focused on some important points of contact between the world of magnetic resonance and that of medical physics, was published during 2021. This Editorial describes and comments on the content of this Focus Issue, which contains articles from leading groups invited by the Guest Editors.

Simple Summary Breast cancer is the most diagnosed cancer for women, and clear surgical margins in breast-conserving surgery (BCS) are essential for preventing recurrence. In this study, the potential of fast field-cycling 1H-NMR relaxometry as a new tool for intraoperative margin assessment was evaluated. The technique allows the determination of the tissue proton relaxation rates as a function of the applied magnetic field on small tissue samples excised from surgical specimens, at the margins of tumour resection, prior to histopathological analysis. It was found that a good accuracy in margin assessment, i.e., a sensitivity of 92% and a specificity of 85%, can be achieved. The discriminating ability shown by the relaxometric assay relies mainly on the difference of fat/water content between healthy and tumour cells. The information obtained has the potential to support the surgeon in real-time margin assessment during BCS. Abstract 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.

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.

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

T 1 relaxation times can be measured at a range of magnetic field strengths by Fast Field-Cycling (FFC) NMR relaxometry to provide T 1 -dispersion curves. These are valuable tools for the investigation of material properties as they provide information about molecular dynamics non-invasively. However, accessing information at fields below 230 μT (10 kHz proton Larmor frequency) requires careful correction of unwanted environmental magnetic fields. In this work a novel method is proposed that compensates for the environmental fields on a FFC-NMR relaxometer and extends the acquisition of Nuclear Magnetic Relaxation Dispersion profiles to 2.3 μT (extremely low field region), with direct application in the study of slow molecular motions. Our method is an improvement of an existing technique, reported by Anoardo and Ferrante in 2003, which exploits the non-adiabatic behaviour of the magnetisation in rapidly-varying magnetic fields and makes use of the oscillation of the signal amplitude to estimate the field strength. This increases the accuracy in measuring the environmental fields and allows predicting the optimal correction values by applying simple equations to fit the data acquired. Validation of the method is performed by comparisons with well-known dispersion curves obtained from polymers and benzene.

Background Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles are phagocytosed by macrophages and when subjected to magnetic resonance imaging (MRI) detect inflammation. We describe a novel MR technique where the magnetic field is rapidly cycled (Fast field-cycling MR, FFC-MR), assessing T1 dispersion over a range of low (100μT-0.2T) fields and offering superior T1-based iron quantification. AIM To quantify iron using the FFC-MR R1 (1/T1) dispersion profile and flow cytometry features of USPIO-laden cells, in comparison to colorimetric assays. Methods Murine J774 macrophage-like cells were incubated with 0–200μg/ml Fe as USPIO (ferumoxytol) for 16 hours, washed and suspended in 500μl PBS/2mM EDTA. Prussian blue staining confirmed USPIO phagocytosis. Relaxation was measured using a clinical, in-house built prototype 0.2T FFC-MR system with a custom test tube coil. R1 dispersion was derived from a saturation recovery sequence (Fig. 1A). R1 (s–1) values were calculated with a monoexponential curve fitting algorithm, R2 of fits were ≥0.999. R1 dispersion profiles were generated plotting R1 against the magnetic field (T). Quantification of side scatter (SCC) intensity and the USPIO-occupied fraction of total cell area was performed with imaging flow cytometry. A colorimetric assay provided validation of cell iron content. All data are mean±SEM, analysed with t-tests, Pearson correlation and linear regression; statistical significance set at p Results Table 1 shows quantitative data derived by all 3 modalities with increasing USPIO exposure. FFC-MR detection of intracellular iron was excellent (p≤0.001 vs. control for all), with separation of average R1 dispersion profiles (Fig. 1B), strong correlation with colorimetry (r=0.993 p USPIO exposure (μg/ml medium) 0 5 10 40 80 100 200 FFC-MR Mean R1 1x106 cell suspension (s–1) 0.308±0.014 0.356±0.013** 0.432±0.016** 0.706±0.021** 1.174±0.031** 1.239±0.033** 1.599±0.041** Flow cytometry USPIO area/cell area 0.034±0.001 0.036±0.001 0.037±0.001* 0.069±0.001** 0.085±0.001** 0.090±0.001** 0.097±0.001** Flow cytometry SSC intensity 26860 32815** 39573** 69285** 80967** 82693** 86373** Colorimetric assay Iron concentration 1x106 cells (ng/μg protein) 0.115±0.118 1.121±0.045** 2.074±0.084** 5.496±0.134** 8.421±0.269** 9.771±0.100** 12.398±0.233** SSC = side-scattered light; *p Conclusion Field-cycling MR is capable of highly accurate intracellular USPIO quantification, which has potential to non-invasively detect clinically relevant amounts of iron in inflammatory cardiovascular diseases. Acknowledgement/Funding NHS Grampian Endowment Fund

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.

Graphical abstract, Highlights • FFC-MR can detect and quantify dependence of macrophage USPIO R1 dispersion in vitro. • Inflammation assessment in vivo and the utility of USPIO may be enhanced by FFC-MR. • Accessing tissue T1 dispersion properties may complement FFC-MR imaging techniques., Purpose Inflammation is central in disease pathophysiology and accurate methods for its detection and quantification are increasingly required to guide diagnosis and therapy. Here we explored the ability of Fast Field-Cycling Magnetic Resonance (FFC-MR) in quantifying the signal of ultra-small superparamagnetic iron oxide particles (USPIO) phagocytosed by J774 macrophage-like cells as a proof-of-principle. Methods Relaxation rates were measured in suspensions of J774 macrophage-like cells loaded with USPIO (0–200 μg/ml Fe as ferumoxytol), using a 0.25 T FFC benchtop relaxometer and a human whole-body, in-house built 0.2 T FFC-MR prototype system with a custom test tube coil. Identical non-imaging, saturation recovery pulse sequence with 90° flip angle and 20 different evolution fields selected logarithmically between 80 μT and 0.2 T (3.4 kHz and 8.51 MHz proton Larmor frequency [PLF] respectively). Results were compared with imaging flow cytometry quantification of side scatter intensity and USPIO-occupied cell area. A reference colorimetric iron assay was used. Results The T1 dispersion curves derived from FFC-MR were excellent in detecting USPIO at all concentrations examined (0–200 μg/ml Fe as ferumoxytol) vs. control cells, p ≤ 0.001. FFC-NMR was capable of reliably detecting cellular iron content as low as 1.12 ng/µg cell protein, validated using a colorimetric assay. FFC-MR was comparable to imaging flow cytometry quantification of side scatter intensity but superior to USPIO-occupied cell area, the latter being only sensitive at exposures ≥ 10 µg/ml USPIO. Conclusions We demonstrated for the first time that FFC-MR is capable of quantitative assessment of intra-cellular iron which will have important implications for the use of USPIO in a variety of biological applications, including the study of inflammation.

Fast field cycling (FFC) offers a unique window on molecular dynamics for in vivo applications, thanks to its ability to measure the NMR dispersion profile. This chapter summarises the different technologies that have been developed to exploit FFC-MRI for biomedical applications since the first attempts around 1990, using a range of technology that has been developed to investigate the rich source of information provided by T1 dispersion. The chapter also discusses how FFC technologies based on resistive coils present some important limitations, including in the design of pulse sequences or in the quality of the data. In addition to reviewing important technologies and methods from a number of techniques in various laboratories, including Overhauser imaging, pre-polarised MRI and delta relaxation-enhanced MRI, we present some of the new challenges that human-sample FFC brings to magnetic resonance imaging (MRI) through illustrations from the recently completed resistive 0.2 T FFC-MRI system developed in the University of Aberdeen FFC laboratory. Finally, this chapter presents some of the promising results from medical studies on cancer, muscle damage and osteoarthritis, illustrating the possibilities offered by FFC-MRI in the search for entirely new biomarkers that might be used to improve the diagnosis and monitoring of disease in the future.

Proton-electron double-resonance imaging (PEDRI) employs electron paramagnetic resonance irradiation with low-field magnetic resonance imaging so that the electron spin polarization is transferred to nearby protons, resulting in higher signals. PEDRI provides information about free radical distribution and, indirectly, about the local microenvironment such as partial pressure of oxygen (pOHigh-power radio frequency irradiation is needed for optimum signal enhancement, which may be harmful to living tissue by unwanted heat deposition. Free radical probes differ depending on the purpose of PEDRI. Some probes are less effective for enhancing signal than others, which can reduce image quality. It is so far not possible to image endogenous radicals by PEDRI because low concentrations and broad line widths of the radicals lead to negligible signal enhancement.PEDRI has similarities with electron paramagnetic resonance imaging (EPRI) because both techniques observe the EPR signal, directly in the case of EPRI and indirectly with PEDRI. PEDRI provides information that is vital to research on homeostasis, development of diseases, or treatment responses in vivo. It is expected that the development of new EPR techniques will give insights into novel PEDRI applications and vice versa. Antioxid. Redox Signal. 28, 1345-1364.

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. Magn Reson Med 73:1120–1124, 2015. © 2014 Wiley Periodicals, Inc.

Purpose Fast Field-Cycling MRI (FFC-MRI) is a novel MRI technique in which the external magnetic field ( B 0 ) is switched during the imaging experiment, always returning to the same value ( B 0 D ) for signal detection. By doing this, FFC-MRI grants access to information which is invisible to conventional MRI scanners, including the variation of T 1 with magnetic field. These measurements, known as T 1 -dispersion, exhibit great promise as a new form of endogenous image contrast, and may have application in the early diagnosis of a range of diseases. Construction of an MR imaging system capable of rapidly switching magnetic fields, and reaching ultra-low fields (200 μT or lower), requires novel magnets, power supplies and control electronics. Here we will describe progress on a whole-body human sized FFC imaging system and preliminary results from a clinical trial imaging acute stroke using FFC-MRI. Methods The magnet (Tesla Engineering Ltd, UK) is of a resistive design with a length of 2 m and an inner bore diameter of 500 mm; it is capable of achieving a maximum field strength ( B 0 D ) of 0.2 T (8.52 MHz proton Larmor frequency). The system can switch between zero and maximum field in 12 ms, corresponding to a maximum dB/dT of 16.7 T/s. The gradients and RF system are controlled by a commercial MRI console (MR Solutions Ltd, UK) while the main magnet coil, shim coils and earth’s-field cancellation coils (necessary for ultra-low field operation) are controlled by a dedicated embedded computer running in-house software written in Labview (National Instruments, US). Results The prototype system has been fully commissioned and is now operational. FFC-MRI imaging of patients (with full ethical permissions granted) using the system has now commenced as part of a clinical study on imaging acute stroke. It is hoped that the new information afforded by FFC-MRI will aid in the detection and assessment of stroke. Conclusions The novel system design described here will allow us to explore the unique T 1 dispersion contrast made available by FFC-MRI. Future work will concentrate on identifying how this newly accessible region of the T 1 dispersion curve can be exploited for clinical diagnosis.

Fast Field-Cycling MRI (FFC-MRI) is an emerging MRI technique that allows the main magnetic field to vary, allowing probing T 1 at various magnetic field strengths. This technique offers promising possibilities but requires long scan times to improve the signal-to-noise ratio. This paper presents an algorithm derived from the two-point method proposed by Edelstein that can estimate T 1 using only one image per field, thereby shortening the scan time by a factor of nearly two, taking advantage of the fact that the equilibrium magnetisation is proportional to the magnetic field strength. Therefore the equilibrium magnetisation only needs measuring once, then T 1 can be found from inversion recovery experiments using the Bloch equations. The precision and accuracy of the algorithm are estimated using both simulated and experimental data, by Monte-Carlo simulations and by comparison with standard techniques on a phantom. The results are acceptable but usage is limited to the case where variations of the main magnetic field are fast compared with T 1 and where the dispersion curve is relatively linear. The speed-up of T 1 -dispersion measurements resulting from the new method is likely to make FFC-MRI more acceptable when it is applied in the clinic.

Purpose The T1 of tissue has a strong dependence on the measurement magnetic field strength. T1-dispersion could be a useful contrast parameter, but is unavailable to clinical MR systems which operate at fixed magnetic field strength. The purpose of this work was to implement a removable insert magnet coil for field-cycling T1-dispersion measurements on a vertical-field MRI scanner, by offsetting the static field over a volume of interest. Methods An insert magnet coil was constructed for use with a whole-body sized 59 milli-Tesla (mT) vertical-field, permanent-magnet based imager. The coil has diameter 38 cm and thickness 6.1 cm and a homogeneous region (± 5%) of 5 cm DSV, offset by 5 cm from the coil surface. Surface radiofrequency (RF) coils were also constructed. Results The insert coil was used in conjunction with a surface RF coil and a volume-localized inversion-recovery pulse sequence to plot T1-dispersion in a human volunteer's forearm over a range of field strengths from 1 mT to 70 mT. Conclusion T1-dispersion measurements were demonstrated on a fixed-field MRI scanner, using an insert coil. This demonstrates the feasibility of relaxation dispersion measurements on an otherwise conventional MR imager, facilitating the exploitation of T1-dispersion contrast for enhanced diagnosis. Magn Reson Med 72:1492–1497, 2014. © 2013 Wiley Periodicals, Inc.

Fast field cycling (FFC) nuclear magnetic resonance (NMR) is applied to probe the slow dynamics of liquid molecules imbibed in porous catalysts. The FFC measurements are used to determine surface diffusion correlation and residence times that provide information on the molecular dynamics of surface adsorbed species. The longitudinal relaxation time T1 dispersion curves reveal biphasic diffusion of adsorbed water that we attribute to the presence of “strongly bound” and “weakly bound” molecules. FFC measurements of organic liquids (2-butanone, 2-propanol) do not show such behavior. These observations agree with molecular dynamics simulations. The frequency dependence of the relaxation time ratio T1/T2 is also considered; it is demonstrated that T1/T2 remains a valid indicator of adsorption energy regardless of the field strength at which the measurement is taken in the range B0 = 0.1 mT to 0.23 T.

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.

The relaxation of 1H nuclei due to their interaction with quadrupolar 14N nuclei in gel structures is measured using fast field-cycling NMR. This phenomenon called quadrupolar dips has been reported in different 1H-14N 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. T1-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 14N 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. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

Magnetisation Transfer Contrast (MTC) is an important MR contrast-generating mechanism to characterise the MR-invisible macromolecular protons using an off-resonance pre-saturation RF irradiation pulse (or MT pulse). MTC MRI is normally implemented at a fixed magnetic field; however, it may be useful to evaluate changes of the MT effect as a function of external magnetic field strength (B₀). In order to conduct field-dependent MTC experiments with a single MR system, two techniques are crucially needed. B₀ should be able to be switched between levels during irradiation of the MT pulse. At the same time, the resonance frequency of the RF coil (f₀) should also be able to be shifted to the corresponding value. Switching B₀ is attained by the fast field-cycling technique, while in order to switch f₀, a specially designed multi-tunable RF coil is required. Here, we designed and constructed an actively frequency-switchable RF coil for frequencies at and below 2.5 MHz. The design employed PIN diodes, and enabled switching f₀ between five different values, with excellent impedance matching (approximately -37 dB S₁₁ reflection) and Q-factor of about 100 at each configuration.

Introduction Diffusion refers to the random Brownian molecular motion. In a bulk liquid, water molecules are free to move and this is characterized by a large value of the diffusion constant, D. The motion of water molecules within cells may be restricted by the cell wall and other structures, resulting in a lower value of D; the same may be true of interstitial fluid in tissues if the cells are densely packed. Diffusion-Weighted Imaging (DWI) generates images based on the variation of D [1] . Diffusion-Weighted MRI DWI uses balanced pulses of magnetic field gradient, applied either side of a 180° pulse within a spin-echo pulse sequence, as introduced by Stejskal and Tanner in 1965 [2] . For stationary spins, any phase accrued during the first gradient pulse is unwound during the second pulse. Spins in random motion, however, become dephased, leading to a diffusion-dependent loss of signal. The signal can be given by S b , TE = M 0 exp - TE T 2 exp - bD where b is a factor which is dependent on the square of gradient strength ( G 2 ), its duration and spacing, known as the “b-value”; the stronger the value of b, the higher is the diffusion weighting [3] . b values in the range 0–1000 s/mm2 are typically used. In a DWI image with a large b-value, tissues containing freely-diffusing water molecules will appear dark (due to loss of signal), while tissues where diffusion is restricted will appear with greater intensity. Conclusions DWI is a standard part of the diagnostic armoury of clinical MRI, where one of its most important applications lies in the diagnosis of cancer. This lecture will describe the basic principles of DWI, with particular emphasis on its use in oncology [4] .

Magnetic resonance imaging (MRI) and fast field-cycling (FFC) NMR are both well-developed methods. The combination of these techniques, namely fast field-cycling magnetic resonance imaging (FFC-MRI) is much less well-known. Nevertheless, FFC-MRI has a number of significant applications and advantages over conventional techniques, and is being pursued in a number of laboratories. This article reviews the progress in FFC-MRI over the last two decades, particularly in the areas of Earth's field and pre-polarised MRI, as well as free radical imaging using field-cycling Overhauser MRI. Different approaches to magnet design for FFC-MRI are also described. The paper then goes on to discuss recent techniques and applications of FFC-MRI, including protein measurement via quadrupolar cross-relaxation, contrast agent studies, localised relaxometry and FFC-MRI with magnetisation-transfer contrast.

Theoretical Overhauser-detected EPR spectra of 14 N and 15 N nitroxide systems in low magnetic field by field-cycled dynamic nuclear polarization (FC-DNP) were described by a combination of DNP theory and a model of FC-DNP. Spectra were simulated at magnetic fields between 0 and 8 mT. The simulations were able to predict both the EPR peak positions and their amplitudes, corresponding to those from FC-DNP experiments with 14 N and 15 N TEMPOL solutions. EPR irradiation was in the 45–133 MHz range while NMR signal detection occurred at a field of 59 mT. At this frequency range, four π transitions of a 14 N system and three π transitions of a 15 N system were observed. The simulation programmes were also used to predict the spectral amplitudes of the FC-DNP with EPR irradiation power in the 1–15 W range. Theoretical FC-DNP systems were in good agreement with experimental results; however, at low magnetic fields the inhomogeneity of our magnet system resulted in the EPR peaks being left-shifted and somewhat broader than those from the theoretical prediction.

In vitro and in vivo measurements of pH and thiols provide critical information on physiology and pathophysiology of living organisms, particularly related to oxidative stress. Stable nitroxides of imidazoline and imidazolidine types provide the unique possibility of measuring local values of pH and glutathione content in various biological systems, including in vivo studies. The basis for these applications is the observation of specific chemical reactions of these nitroxides with protons or thiols, followed by significant changes in the electron paramagnetic resonance (EPR) spectra of these probes, measured by low-frequency EPR techniques. The applications of some newly developed pH and SH probes in model systems of pharmacological interest, biological fluids, tissues, and cells as well as in vivo studies in isolated hearts and in the gut of living animals are discussed.

Along with significant progress in low-frequency electron spin resonance (ESR, also called electron paramagnetic resonance, EPR), other techniques such as Longitudinally-Detected ESR (LODESR), proton electron double-resonance imaging (PEDRI) and field-cycled dynamic nuclear polarization (FC-DNP) have been developed forin vivoapplications. However their potential is still far from maximally defined, in part, because of the need for new specific function-directed spin probes. An application of stable nitroxides of imidazoline and imidazolidine types provides unique possibility to measure local values of pH and thiol content in various biological systems, includingin vivostudies. These applications are based on the observation of specific chemical reactions of these nitroxides with protons or thiols, followed by significant changes in their EPR spectra. To increase sensitivity of pH probes for low-frequency EPR spectroscopy we evaluated two alternative approaches: (i) application of isotopically substituted labels, and (ii) acquisition of EPR spectra at high modulation amplitude. Spatial and spectral-spatial imaging (pH-mapping) using PEDRI and L-band EPR imagers were performed both on phantom samples andin vivo. The applications of the pH and SH probes in model systems, biological fluids, andin vivoin living animals are discussed.

Proton electron double resonance imaging (PEDRI) measures the spatial distribution of paramagnetic species in biological samples using the Overhauser effect. Triaryl methyl (TAM) free radicals have been developed as a spin probe for PEDRI since they have very long T1e. Therefore, low RF power levels are sufficient to saturate the electron spin system with resultant high NMR enhancement facilitating application of PEDRI in living animals. In this report, PEDRI studies were performed at 0.02 T. The power-dependent image enhancement was studied using phantoms of TAM in saline, then the distribution and pharmacokinetics of TAM in living mice were measured. Following intravenous administration of 0.7 mmol/kg of TAM, enhancements of up to −34 were observed enabling visualization of its distribution within the body. Maximum uptake of TAM in the vascular compartment was seen 1 min postadministration with half-clearance within 5 min. Maximum uptake in the kidneys occurred at 10 min with half-clearance at 26 min and maximum accumulation in the bladder after 50 min. Thus, TAM is initially compartmentalized in the vasculature and this is followed by rapid uptake and excretion by the kidneys. PEDRI enabled rapid imaging of the distribution and clearance of this paramagnetic probe and this information should facilitate the use of TAM as a label for oximetry and other applications. Magn Reson Med 48:530–534, 2002. © 2002 Wiley-Liss, Inc.

A new pulse sequence for rapid imaging of free radicals is presented which combines snapshot imaging methods and conventional field-cycled proton electron double resonance imaging (FC-PEDRI). The new sequence allows the number of EPR irradiation periods to be optimized to obtain an acceptable SNR and spatial resolution of free radical distribution in the final image while reducing the RF power deposition and increasing the temporal resolution. Centric reordered phase encoding has been employed to counter the problem of rapid decay of the Overhauser-enhanced signal. A phase-correction scheme has also been used to correct problems arising from instability of the magnetic field following field-cycling. In vivo experiments were carried out using triaryl methyl free radical contrast agent, injected at a dose of 0.214 mmol kg(-1) body weight in anaesthetized adult male Sprague-Dawley rats. Transaxial images through the abdomen were collected using 1, 2, 4 and 8 EPR irradiation periods. Using 4 EPR irradiation periods it was possible to generate free radical distributions of acceptable SNR and resolution. The EPR power deposition is reduced by a factor of 16 and the acquisition time is reduced by a factor of 4 compared to an acquisition using the conventional FC-PEDRI pulse sequence.

Proton electron double resonance imaging (PEDRI) uses the Overhauser effect to image the distribution of free-radicals in biological samples and animals. Standard MRI hardware and software is used, with the addition of hardware to irradiate the free-radical-of-interest's EPR resonance. For in vivo applications it must be implemented at a sufficiently low magnetic field to result in an EPR irradiation frequency that will penetrate the sample but will not cause excessive nonresonant power deposition therein. Many clinical MRI systems use resistive magnets that are capable of operating at 10-20 mT, and which could thus be used as PEDRI imagers with the addition of a small amount of extra hardware. This article describes the conversion of a 0.38 T whole-body MRI system for operation as a 20.1 mT small-animal PEDRI imager. The magnet power supply control electronics required a small modification to operate at the lower field strength, but no permanent hardware changes to the MRI console were necessary, and no software modification was required. Frequency down- and up-conversion was used on the NMR RF system, together with a new NMR/EPR dual-resonance RF coil assembly. The system was tested on phantoms containing free-radical solution, and was also used to image the distribution of a free-radical contrast agent injected intravenously into anesthetized mice.

There is growing interest in the use of magnetic resonance imaging (MRI) to examine solid materials where the restricted motion of the probed spins leads to broad lines and short T2 values, rendering many interesting systems invisible to conventional 2DFT pulsed imaging methods. In EPR T2 seldom exceeds 0.1 μs and continuous-wave methods are adopted for spectroscopy and imaging. In this paper we demonstrate the use of continuous-wave MRI to obtain 2-dimensional images of short T2 samples. The prototype system can image samples up to 50 mm in diameter by 60 mm long and has been used to image polymers and water penetration in porous media. Typical acquisition times range between 10 and 40 min. Resolution of 1 to 2 mm has been achieved for samples with T2 values ranging from 38 to 750 μs. There is the possibility of producing image contrast that is determined by the material properties of the sample.

The nitrogen monoxide radical (NO ) forms paramagnetic mono- and dinitrosyl–iron complexes in biologic tissues. To establish a noninvasive technique for in vivo NO imaging, we evaluated the suitability of these complexes as magnetic resonance (MR) contrast agents, making use of the ability of the unpaired electrons of the complexes to enter into dynamic nuclear polarization with water protons and hence produce enhancement on images generated by the technique of proton-electron–double-resonance imaging (PEDRI). Phantom solutions of synthetic nitrosyl–iron complexes (NICs) altered the signal intensity of PEDRI images. The dinitrosyl–iron complex (DNIC) with serum albumin induced a significantly larger signal alteration than the mononitrosyl–iron complex (MNIC) with dithiocarbamate. Exposure of rat liver to sodium nitroprusside (SNP) by ex vivo and in situ perfusion induced a composite X-band electron spin resonance (ESR) spectrum of the isolated liver characteristic of a MNIC and DNIC. On storage of the tissue, the MNIC signal disappeared and the DNIC signal intensity increased. Correspondingly, in cross-sectional PEDRI images taken at room temperature, the SNP-exposed livers initially exhibited a weak signal that strongly increased with time. In conclusion, NICs can be detected using PEDRI and could be exploited for in vivo NO imaging.

The multimodality approach to in vivo detection of free radicals combines the relative benefits of three free radical detection modalities: conventional RF CW-ESR, LODESR and PEDRI. We have built apparatus capable of combining these modalities to allow sequential PEDRI and CW-ESR, sequential LODESR and proton NMR imaging and simultaneous LODESR and CW-ESR. These systems offer superior performance in terms of both the scope and quality of information over single-modality free radical detection systems.

Proton-electron double-resonance imaging (PEDRI) has considerable value for study of the distribution and elimination pathways of nitroxide free radicals (NFRs). This has been illustrated by its use in studies of kidney function in the living rat in which the NFR proxyl carboxylic acid (PCA) has been employed as a 'tracer'. The technique, at its present stage of development, can demonstrate location of PCA in enough detail to observe the passage through kidney cortex and medulla differentially, and to see the NFR within the major abdominal blood vessels. These studies are helping towards an understanding of the metabolic fate of PCA, as well as providing information about kidney performance after challenge with a nephrotoxin. In addition, nitric oxide complexes, formed in vivo by providing rats with a nitrite-rich diet, have been observed ex vivo using PEDRI and field-cycled DNP.

The design, construction and use of a large-scale field-cycled proton-electron double-resonance imaging (FC-PEDRI) imager is described. The imager is based on a whole-body sized, vertical field, 59 mT permanent magnet. Field cycling is accomplished by the field compensation method, and uses a secondary, resistive magnet with an internal diameter of 52 cm. The magnetic field can be switched from zero to 59 mT or vice versa in 40 ms. It is used with a double-resonance coil assembly (NMR/EPR) comprising a solenoidal NMR transmit/receive coil and a coaxial, external birdcage resonator for EPR irradiation. Experiments to image the distribution of an exogenous nitroxide free radical in anaesthetized rabbits are described.

We describe a submicrosecond resonator and receiver system for use in pulsed magnetic resonance at 220 MHz. This new resonator and receiver system design enables a reduction of the dead time, and in principle its complete elimination. We show experimentally that the resonator and receiver system permits the detection of free induction decay signals 300 ns from the end of the transmitting pulse, even with large (55-ml) saline samples. This apparatus was specifically developed for in vivo Fourier transform electron paramagnetic resonance detection of free radicals; however, it can also be used in pulsed nuclear magnetic resonance imaging of solids with applications in materials research and the polymer industry.

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.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.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.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.

Fast Field-Cycling MRI (FFC-MRI) is an emerging MRI technique that allows the main magnetic field to vary, allowing probing T1 at various magnetic field strengths. This technique offers promising possibilities but requires long scan times to improve the signal-to-noise ratio. This paper presents an algorithm derived from the two-point method proposed by Edelstein that can estimate T1 using only one image per field, thereby shortening the scan time by a factor of nearly two, taking advantage of the fact that the equilibrium magnetisation is proportional to the magnetic field strength. Therefore the equilibrium magnetisation only needs measuring once, then T1 can be found from inversion recovery experiments using the Bloch equations. The precision and accuracy of the algorithm are estimated using both simulated and experimental data, by Monte-Carlo simulations and by comparison with standard techniques on a phantom. The results are acceptable but usage is limited to the case where variations of the main magnetic field are fast compared with T1 and where the dispersion curve is relatively linear. The speed-up of T1-dispersion measurements resulting from the new method is likely to make FFC-MRI more acceptable when it is applied in the clinic.

The T(1) of tissue has a strong dependence on the measurement magnetic field strength. T(1) -dispersion could be a useful contrast parameter, but is unavailable to clinical MR systems which operate at fixed magnetic field strength. The purpose of this work was to implement a removable insert magnet coil for field-cycling T(1) -dispersion measurements on a vertical-field MRI scanner, by offsetting the static field over a volume of interest.An insert magnet coil was constructed for use with a whole-body sized 59 milli-Tesla (mT) vertical-field, permanent-magnet based imager. The coil has diameter 38 cm and thickness 6.1 cm and a homogeneous region (± 5%) of 5 cm DSV, offset by 5 cm from the coil surface. Surface radiofrequency (RF) coils were also constructed.The insert coil was used in conjunction with a surface RF coil and a volume-localized inversion-recovery pulse sequence to plot T(1) -dispersion in a human volunteer's forearm over a range of field strengths from 1 mT to 70 mT.T(1) -dispersion measurements were demonstrated on a fixed-field MRI scanner, using an insert coil. This demonstrates the feasibility of relaxation dispersion measurements on an otherwise conventional MR imager, facilitating the exploitation of T(1) -dispersion contrast for enhanced diagnosis.

We report the modification of a low-field whole-body NMR imager to allow radio frequency EPR spectroscopy. The instrument is designed to give optimum sensitivity for in vivo detection of free radicals. The RF circuit is able to operate over a wide frequency range (240 - 320 MHz) and is designed to handle input power levels of up to 12.5 W. The EPR resonator is of the loop - gap type suitable for samples up to 400 ml. A remote resonator coupling method has been developed enabling convenient matching adjustment. An automatic frequency control circuit is able to adjust for frequency deviations caused by animal motion. Where possible, existing imager hardware and commercially available instruments have been used. The instrument is controlled from a central computer via an IEEE 488 instrumentation bus. Here we present sensitivity measurements obtained from a variety of large aqueous samples containing nitroxide free radicals. We show that the instrument is suitable for the detection of exogenous free radicals in 200 g rats.