This study investigated nine combination methods produced from three interpolation (Lanczos, iterative curvature based interpolation, and contrast-guided) and three segmentation (spatial fuzzy C-means, modified fuzzy C-means [mFCM], and level set method) models from optic nerve magnetic resonance images (MRI). The aim was to produce sharp edges of the optic nerves for cross-sectional area measurement. Lanczos-mFCM was identified as the best combination in terms of: image quality; Dice similarity coefficient; a similar area compared with measurements from raw images but with higher reproducibility; and the highest signal-to-noise and contrast-to-noise ratios. It was then applied to ten normal datasets. The mean cross-sectional areas were 12.57 +/- 1.92mm2 from proton density images, 12.98 +/- 2.18mm2 from T2-weighted (T2W) images including the optic nerve sheath, and 1.68 +/- 0.69mm2 from the T2W images of the optic nerve only. The Lanczos-mFCM method is recommended for future quantitative studies on optic nerve MRI.

Delivering therapies to deeply seated brain tumours (BT) is a major clinical challenge.Magnetic drug targeting (MDT) could overcome this by rapidly transporting magnetised drugs directly into BT.We have developed a magnetic device for application in murine BT models using an array of neodymium magnets with a combined strength of 0.7T.In a closed fluidic system, the magnetic device trapped magnetic nanoparticles (MNP) up to distances of 0.8cm.In mice, the magnetic device guided intravenously administered MNP (<50nm) from the circulation into the brain where they localised within mouse BT.Furthermore, MDT of magnetised Temozolomide (TMZ mag+ ) significantly reduced tumour growth and extended mouse survival to 48 days compared to the other treatment groups.Using the same principles, we built a proof of principle scalable magnetic device for human use with a strength of 1.1T.This magnetic device demonstrated trapping of MNP undergoing flow at distances up to 5cm.MDT using our magnetic device provides an opportunity for targeted delivery of magnetised drugs to human BT.

This review describes targeted magnetic resonance imaging (tMRI) of small changes in the T-1 and the spatial properties of normal or near normal appearing white or gray matter in disease of the brain. It employs divided subtracted inversion recovery (dSIR) and divided reverse subtracted inversion recovery (drSIR) sequences to increase the contrast produced by small changes in T-1 by up to 15 times compared to conventional T-1-weighted inversion recovery (IR) sequences such as magnetization prepared-rapid acquisition gradient echo (MP-RAGE). This increase in contrast can be used to reveal disease with only small changes in T-1 in normal appearing white or gray matter that is not apparent on conventional MP-RAGE, T-2-weighted spin echo (T-2-wSE) and/or fluid attenuated inversion recovery (T2-FLAIR) images. The small changes in T-1 or T-2 in disease are insufficient to produce useful contrast with conventional sequences. To produce high contrast dSIR and drSIR sequences typically need to be targeted for the nulling TI of normal white or gray matter, as well as for the sign and size of the change in T-1 in these tissues in disease. The dSIR sequence also shows high signal boundaries between white and gray matter. dSIR and drSIR are essentially T-1 maps. There is a nearly linear relationship between signal and T-1 in the middle domain (mD) of the two sequences which includes T(1)s between the nulling T(1)s of the two acquired IR sequences. The drSIR sequence is also very sensitive to reductions in T-1 produced by Gadolinium based contrast agents (GBCAs), and when used with rigid body registration to align three-dimensional (3D) isotropic pre and post GBCA images may be of considerable value in showing subtle GBCA enhancement. In serial MRI studies performed at different times, the high signal boundaries generated by dSIR and drSIR sequences can be used with rigid body registration of 3D isotropic images to demonstrate contrast arising from small changes in T-1 (without or with GBCA enhancement) as well as small changes in the spatial properties of normal tissues and lesions, such as their site, shape, size and surface. Applications of the sequences in cases of multiple sclerosis (MS) and methamphetamine dependency are illustrated. Using targeted narrow mD dSIR sequences, widespread abnormalities were seen in areas of normal appearing white matter shown with conventional T-2-wSE and T-2-FLAIR sequences. Understanding of the features of dSIR and drSIR images is facilitated by the use of their T-1-bipolar filters; to explain their targeting, signal, contrast, boundaries, T-1 mapping and GBCA enhancement. Targeted MRI (tMRI) using dSIR and drSIR sequences may substantially improve clinical MRI of the brain by providing unequivocal demonstration of abnormalities that are not seen with conventional sequences.

This study aims to investigate the presence of evoked action potentials in the human optic nerve using magnetic resonance imaging (MRI). The detection method is based on the effect of the evoked action potentials, which produce the axonal current flowing through the optic nerve. It produces a minute axonal magnetic field around the optic nerve. The axonal current is expected to be generated at the same frequency as the evoked action potentials, which are at the same frequency as the visual stimulus during imaging. This study attempted to detect the axonal magnetic field variation which interacts with the MR main magnetic field, B 0 , and produces signal modulation during image acquisition. Consequently, there will be intra-voxel dephasing within the region of interest (ROI) in the optic nerve. The signal variation can be found by converting the time series signal into the frequency domain using a fast Fourier transform (FFT). The checkerboard visual stimulus was projected to the subject in synchronization with MRI using a gradient echo – echo planar imaging (GE-EPI) sequence. A total of five healthy volunteers and five optic neuritis patients were recruited for this study. The visual stimulus response was only found in one out of the five healthy volunteers, with an estimated axonal field of 7 nT. No response was found in the optic neuritis patients as expected due to the effects of the disease on optic nerve signaling. Clinical Relevance – This study measured the evoked action potentials in the optic nerve which will allow further study into the effects of optic neuritis on optic nerve signaling.

Sperm motility varies between ejaculates from different men and from individual men. We studied normozoospermic and asthenozoospermic ejaculates after density-gradient centrifugation washing (DCG, 80/40%) and compared high- (80%) and low (40%)-motility sperm populations within the same sample. Our objective was to identify differences in endogenous metabolomes and energy metabolism in relation to sperm motility. 1H-Nuclear Magnetic Resonance spectroscopy (NMR) measured the endogenous metabolome of live human sperm. Incubating sperm with 13C-labelled substrates detected energy metabolism by 13C-NMR. The study examined 850 ejaculates and diagnosed asthenozoospermia in 6.1%. DGC was used to wash 160 normozoospermic (N) and 52 asthenozoospermic (A) ejaculates to recover high-motility sperm from the pellet (80N/80A) and low motility from the interface (40N/40A). 1H-NMR spectra, 45(N) and 15(A), were binned and the integrals normalised by sperm concentration. Sperm from 126(N) and 36(A) ejaculates were incubated with either 13C-glucose, 13C-fructose or 13C-pyruvate. 13C-NMR lactate and bicarbonate integrals were normalised by motile or vital sperm concentrations. 1H-NMR spectra choline integrals from the 80A population were significantly lower than the 80N, P  < 0.0001. 13C-substrate conversion to lactate was significantly higher for 40A sperm than 80A sperm when normalised by motile sperm concentration. Bicarbonate integrals were sporadically observed. Sperm from asthenozoospermic ejaculates had similar glycolytic requirements to normozoospermic ones, with larger differences observed between 40 and 80% sperm populations. Higher lactate levels produced by 40% sperm may indicate that impaired sperm motility is due to dysregulated energy metabolism. The alteration in choline metabolism provides opportunities to understand the aetiology of asthenozoospermia. Lay summary How well sperm swim (motility) varies between ejaculates from different men? Normal sperm motility is beneficial to conception and some men diagnosed with infertility have low sperm motility. Sperm metabolise molecules to produce the energy required for motility. We measured concentrations of molecules within sperm and metabolism of molecules given to sperm and related these to the proportion of motile sperm. The study examined 850 sperm samples and found low motility in 6.1%. Metabolism of molecules given to sperm was similar between low and normal motility sperm samples. However, when the most motile sperm were separated from the rest, they were more efficient in metabolising these molecules to achieve motility. Lower concentrations of a molecule called choline were found in low-motility sperm samples compared to normal samples. Choline is associated with cell membranes, energy metabolism and oxidative stress, which may give opportunities to understand the causes of low motility.

The optic nerve is known to be one of the largest nerve bundles in the human central nervous system. There have been many studies of optic nerve imaging and post-processing that have provided insights into pathophysiology of optic neuritis related to multiple sclerosis and neuromyelitis optica spectrum disorder, glaucoma, and Leber's hereditary optic neuropathy. There are many challenges in optic nerve imaging, due to the morphology of the nerve through its course to the optic chiasm, its mobility due to eye movements and the high signal from cerebrospinal fluid and orbital fat surrounding the optic nerve. Recently, many advanced and fast imaging sequences have been used with post-processing techniques in attempts to produce higher resolution images of the optic nerve for evaluating various diseases. Magnetic resonance imaging (MRI) is one of the most common imaging methodologies for the optic nerve. This review paper will focus on recent MRI advances in optic nerve imaging and explain several post-processing techniques being used for analysis of optic nerve images. Finally, some challenges and potential for future optic nerve studies will be discussed.

This study showed an alternative and non-invasive method for measuring brainwaves using Magnetic Resonance Imaging (MRI) with a gradient echo - echo planar imaging (GE-EPI) sequence. An attempt was made to measure the axonal magnetic fields of delta and theta waves using direct detection with MRI. Time-varying brainwaves produce an axonal current which may induce a magnetic field according to the Biot-Savart law. The MR scanner can detect inhomogeneous magnetic fields caused by weak currents generated in a subject that interact with the main magnetic field, $B_{o}$ , of the scanner. Fifteen healthy volunteers were scanned with closed eyes in a dark imaging room. The GE-EPI sequence was used to acquire 1500 time frame images in an axial plane on a 3.0 T Philips scanner. A Butterworth bandstop filter was applied to filter out physiological signals before the detection of brainwave signals. Fast Fourier Transform (FFT) was used to produce frequency spectra where the brainwave frequencies could be detected. Our study measured an axonal magnetic field of 1.5 ± 0.2 nT for the delta waves and 1.5 ± 0.3 nT for the theta waves. Delta waves were found in the range 1.5–4.0 Hz and theta waves in the range 4.0–6.5 Hz. The waves were found on both sides of the occipital lobe, temporal lobe, and hippocampus. We detected more theta waves (2.1% of the brain slice with 5 mm thickness) than delta waves (1.5% of the brain slice with 5 mm thickness). PLCC for the % $\vert \Delta S/S_{eq}\vert $ between the delta and theta waves was 0.7584 at $p =0.001$ significance level and 95% confidence level. We also applied Short Time Fourier Transform (STFT) with epoch lengths of 3.85 s, 7.7 s, and 30.8 s. But the appearance of brainwave signals was not as clear as using FFT over the entire imaging duration.

Dissolution dynamic nuclear polarisation (dDNP) of 13 C-labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised 13 C-labelled pyruvate (13 C1 -pyruvate) and urea (13 C-urea), a nonmetabolised marker. A general mathematical model of pyruvate-lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, Kip , and the forward and reverse fractional rate constants for pyruvate-lactate signal exchange, kpl and klp . An analogous model was developed for urea, enabling estimation of urea tumour losses and the blood clearance parameter, Kiu . A spectral fitting procedure to blood time-course data proved superior to assuming a gamma-variate form for the AIFs. Mean arterial blood pressure marginally correlated with clearance rates. Kiu equalled Kip , indicating equivalent permeability of the tumour vasculature to urea and pyruvate. Fractional loss rate constants due to effluxes of pyruvate, lactate and urea from tumour tissue into blood (kpo , klo and kuo , respectively) indicated that T1 s and the average flip angle, θ, obtained from arterial blood were poor surrogates for these parameters in tumour tissue. A precursor-product model, using the tumour pyruvate signal time-course as the input for the corresponding lactate signal time-course, was modified to account for the observed delay between them. The corresponding fractional rate constant, kavail , most likely reflected heterogeneous tumour microcirculation. Loss parameters, estimated from this model with different TRs, provided a lower limit on the estimates of tumour T1 for lactate and urea. The results do not support use of hyperpolarised urea for providing information on the tumour microcirculation over and above what can be obtained from pyruvate alone. The results also highlight the need for rigorous processes controlling signal quantitation, if absolute estimations of biological parameters are required.

OBJECTIVES:MR imaging of neonates is difficult for many reasons and a major factor is safe transport to the MR facilities. In this article we describe the use of a small, investigational 3-T MR customised for brain imaging and sited on a neonatal unit of a tertiary centre in the UK, which is in contrast to a 300-m journey to the whole-body MR scanner used at present for clinical cases.METHODS:We describe our methods for preparing babies for safe transport and scanning on an investigational 3-T MR scanner on a neonatal unit and the development of appropriate MR sequences. The MR scanner does not have CE marking at present so this early development work was undertaken on normal neonates whose parents consented to a research examination.RESULTS:Fifty-two babies were scanned and there were no serious adverse events. The MR examinations were considered to be diagnostically evaluable in all 52 cases and in 90% the imaging was considered to be at least as good as the quality obtained on the 1.5-T scanner currently used for clinical cases.CONCLUSION:We have shown that this investigational 3-T MR scanner can be used safely on a neonatal unit and we have refined the MR sequences to a point that they are clinically usable.KEY POINTS:• Access to neonatal MR imaging is limited. • We describe an investigational 3-T MR scanner site on a neonatal unit. • The scanner produces images suitable for clinical practice.

A major challenge in preventing preterm birth (PTB) is identifying women at greatest risk. This pilot study prospectively examined the differences in vaginal microbiota and metabolite profiles of women who delivered prematurely compared to their term counterparts in a cohort of asymptomatic (studied at 20–22, n = 80; and 26–28 weeks, n = 41) and symptomatic women (studied at 24–36 weeks, n = 37). Using 16S rRNA sequencing, the vaginal microbiota from cervicovaginal fluid samples was characterized into five Community State Types (CST) dominated by Lactobacillus spp.: CSTI (Lactobacillus crispatus), CSTII (Lactobacillus gasseri), CSTIII (Lactobacillus iners), CSTV (Lactobacillus jensenii); and mixed anaerobes—CSTIV. This was then related to the vaginal metabolite profile and pH determined by 1H-Nuclear Magnetic Resonance spectroscopy and pH indicator paper, respectively. At 20–22 weeks, the term-delivered women (TDW) indicated a proportion of CSTI-dominated microbiota >2-fold higher compared to the preterm-delivered women (PTDW) (40.3 vs. 16.7%, P = 0.0002), and a slightly higher proportion at 26–28 weeks (20.7 vs. 16.7%, P = 0.03). CSTV was >2-fold higher in the PTDW compared to TDW at 20–22 (22.2 vs. 9.7%, P = 0.0002) and 26–28 weeks (25.0 vs. 10.3%, P = 0.03). Furthermore, at 26–28 weeks no PTDW had a CSTII-dominated microbiome, in contrast to 28% of TDW (P < 0.0001). CSTI-dominated samples showed higher lactate levels than CSTV at 20–22 weeks (P < 0.01), and 26–28 weeks (P < 0.05), while CSTII-dominated samples indicated raised succinate levels over CSTV at 26–28 weeks (P < 0.05). These were supported by Principal coordinates analysis, which revealed strong clustering of metabolites according to CST. In addition, the CSTI-dominated samples had an average pH of 3.8, which was lower than those of CSTII—4.4, and CSTV—4.2 (P < 0.05). Elevated vaginal lactate and succinate were associated with predominance of CSTI and II over CSTV in women who delivered at term compared with their preterm counterparts. This suggests that L. jensenii-dominance and decreased lactate and/or succinate could increase the risk of PTB, while L. crispatus/gasseri may confer some protection against inflammation-associated PTB and highlight the need for further study in this area.

Poor sperm motility is a common cause of male infertility for which there are no empirical therapies. Sperm motility is powered by adenosine triphosphate but the relative importance of lactate fermentation and Oxidative Phosphorylation (OxPhos) is debated. To study the relationship between energy metabolism and sperm motility we used dissolution Dynamic Nuclear Polarization (dDNP) for the first time to show the rapid conversion of 13C1-pyruvate to lactate and bicarbonate, indicating active glycolytic and OxPhos metabolism in sperm. The magnitude of both lactate and bicarbonate signals were positively correlated with the concentration of progressively motile sperm. After controlling for sperm concentration, increased progressive sperm motility generated more pyruvate conversion to lactate and bicarbonate. The technique of dDNP allows ‘snapshots’ of sperm metabolism to be tracked over the different stages of their life. This may provide help to uncover the causes of poor sperm motility and suggest new approaches for novel treatments or therapies.

PurposeA rat model was developed to enable direct administration of hyperpolarized 13C‐labeled molecules into a tumor‐supplying artery for magnetic resonance spectroscopy (MRS) studies of tumor metabolism.MethodsRat P22 sarcomas were implanted into the right inguinal fat pad of BDIX rats such that the developing tumors received their principle blood supply directly from the right superior epigastric artery. Hyperpolarized 13C‐molecules were either infused directly to the tumor through the epigastric artery or systemically through the contralateral femoral vein. Spectroscopic data were obtained on a 7 Tesla preclinical scanner.ResultsIntra‐arterial infusion of hyperpolarized 13C‐pyruvate increased the pyruvate tumor signal by a factor of 4.6, compared with intravenous infusion, despite an approximately 7 times smaller total dose to the rat. Hyperpolarized glucose signal was detected at near‐physiological systemic blood concentration. Pyruvate to lactate but not glucose to lactate metabolism was detected in the tumor. Hyperpolarized 13C‐labeled combretastatin A1 diphosphate, a tumor vascular disrupting agent, showed an in vivo signal in the tumor.ConclusionsThe model maximizes tumor substrate/drug delivery and minimizes T1 relaxation signal losses in addition to systemic toxicity. Therefore, it permits metabolic studies of hyperpolarized substrates with relatively short T1 and opens up the possibility for preclinical studies of hyperpolarized drug molecules. Magn Reson Med 78:2116–2126, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

A wireless accelerometer has been used in conjunction with a dedicated 3T neonatal MRI system installed on a Neonatal Intensive Care Unit to measure in-plane rotation which is a common problem with neonatal MRI. Rotational data has been acquired in real-time from phantoms simultaneously with MR images which shows that the wireless accelerometer can be used in close proximity to the MR system. No artifacts were observed on the MR images from the accelerometer or from the MR system on the accelerometer output. Initial attempts to correct the raw data using the measured rotational angles have been performed, but further work will be required to make a robust correction algorithm.

Preterm birth (PTB) may be preceded by changes in the vaginal microflora and metabolite profiles.

An efficient synthesis of [3-13C]-2,3-dihydroxy-4-methoxybenzaldehyde, an isotopically labelled probe of a common intermediate used in the synthesis of a number of biologically relevant molecules, has been achieved in 9 steps from an acyclic, non-aromatic precursor. A 13C label for molecular imaging was introduced in a linear synthesis from the reaction of [13C]-labelled methyl iodide with glutaric monomethyl ester chloride. Cyclisation then aromatisation gave 1,3-dimethoxybenzene and an additional methoxy group was introduced by a formylation/Baeyer–Villiger/hydrolysis/methylation sequence. Subsequent ortho-formylation and selective demethylation yielded the desired [3-13C]-2,3-dihydroxy-4-methoxybenzaldehyde.

Changes in vaginal microbiota that is associated with preterm birth (PTB) leave specific metabolite fingerprints that can be detected in the cervicovaginal fluid (CVF) using metabolomics techniques. In this study, we characterize and validate the CVF metabolite profile of pregnant women presenting with symptoms of threatened preterm labor (PTL) by both 1H-nuclear magnetic resonance spectroscopy (NMR) and enzyme-based spectrophotometry. We also determine their predictive capacity for PTB, singly, and in combination, with current clinical screening tools- cervicovaginal fetal fibronectin (FFN) and ultrasound cervical length (CL). CVF was obtained by high-vaginal swabs from 82 pregnant women with intact fetal membranes presenting between 24 and 36 weeks gestation with symptoms of threatened, but not established, PTL. Dissolved CVF samples were scanned with a 400 MHz NMR spectrometer. Acetate and other metabolites were identified in the NMR spectrum, integrated for peak area, and normalized to the total spectrum integral. To confirm and validate our observations, acetate concentrations (AceConc) were also determined from a randomly-selected subset of the same samples (ri = 57), by spectrophotometric absorption of NADH using an acetic acid assay kit. CVF FFN level, transvaginal ultrasound CL, and vaginal pH were also ascertained. Acetate normalized integral and AceConc were significantly higher in the women who delivered preterm compared to their term counterparts (P = 0.002 and P = 0.006, respectively). The 'H-NMR-derived acetate integrals were strongly correlated with the AceConc estimated by spectrophotometry (r = 0.69; P < 0.0001). Both methods were equally predictive of PTB <37 weeks (acetate integral: AUC = 0.75, 95% Cl = 0.60-0.91; AceConc: AUC = 0.74, 95% CI = 0.57-0.90, optimal predictive cutoff of >0.53 g/I), and of delivery within 2 weeks of the index assessment (acetate integral: AUC = 0.77, 95% CI = 0.580.96; AceConc: AUC = 0.68, 95% CI = 0.5-0.9). The predictive accuracy of CVF acetate was similar to CL and FFN. The combination of CVF acetate, FFN, and ultrasound CL in a binary logistic regression model improved the prediction of PTB compared to the three markers individually, but CVF acetate offered no predictive improvement over ultrasound CL combined with CVF FFN. Elevated CVF acetate in women with symptoms of PTL appears predictive of preterm delivery, as well as delivery within 2 weeks of presentation. An assay of acetate in CVF may prove of clinical utility for predicting PTB.