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Purpose To develop a postprocessing algorithm for multiecho chemical-shift encoded water–fat separation that estimates proton density fat fraction (PDFF) maps over the full dynamic range (0-100%) using multipeak fat modeling and multipoint search optimization. To assess its accuracy, reproducibility, and agreement with state-of-the-art complex-based methods, and to evaluate its robustness to artefacts in abdominal PDFF maps. Methods We introduce MAGO (MAGnitude-Only), a magnitude-based reconstruction that embodies multipeak liver fat spectral modeling and multipoint optimization, and which is compatible with asymmetric echo acquisitions. MAGO is assessed first for accuracy and reproducibility on publicly available phantom data. Then, MAGO is applied to N = 178 UK Biobank cases, in which its liver PDFF measures are compared using Bland-Altman analysis with those from a version of the hybrid iterative decomposition of water and fat with echo asymmetry and least squares estimation (IDEAL) algorithm, LiverMultiScan IDEAL (LMS IDEAL, Perspectum Diagnostics Ltd, Oxford, UK). Finally, MAGO is tested on a succession of high field challenging cases for which LMS IDEAL generated artefacts in the PDFF maps. Results Phantom data showed accurate, reproducible MAGO PDFF values across manufacturers, field strengths, and acquisition protocols. Moreover, we report excellent agreement between MAGO and LMS IDEAL for 6-echo, 1.5 tesla human acquisitions (bias = −0.02% PDFF, 95% confidence interval = ±0.13% PDFF). When tested on 12-echo, 3 tesla cases from different manufacturers, MAGO was shown to be more robust to artefacts compared to LMS IDEAL. Conclusion MAGO resolves the water–fat ambiguity over the entire fat fraction dynamic range without compromising accuracy, therefore enabling robust PDFF estimation where phase data is inaccessible or unreliable and complex-based and hybrid methods fail.

As the burden of liver disease reaches epidemic levels, there is a high unmet medical need to develop robust, accurate and reproducible non-invasive methods to quantify liver tissue characteristics for use in clinical development and ultimately in clinical practice. This prospective cross-sectional study systematically examines the repeatability and reproducibility of iron-corrected T1 (cT1), T2*, and hepatic proton density fat fraction (PDFF) quantification with multiparametric MRI across different field strengths, scanner manufacturers and models. 61 adult participants with mixed liver disease aetiology and those without any history of liver disease underwent multiparametric MRI on combinations of 5 scanner models from two manufacturers (Siemens and Philips) at different field strengths (1.5T and 3T). We report high repeatability and reproducibility across different field strengths, manufacturers, and scanner models in standardized cT1 (repeatability CoV: 1.7%, bias -7.5ms, 95% LoA of -53.6 ms to 38.5 ms; reproducibility CoV 3.3%, bias 6.5 ms, 95% LoA of -76.3 to 89.2 ms) and T2* (repeatability CoV: 5.5%, bias -0.18 ms, 95% LoA -5.41 to 5.05 ms; reproducibility CoV 6.6%, bias -1.7 ms, 95% LoA -6.61 to 3.15 ms) in human measurements. PDFF repeatability (0.8%) and reproducibility (0.75%) coefficients showed high precision of this metric. Similar precision was observed in phantom measurements. Inspection of the ICC model indicated that most of the variance in cT1 could be accounted for by study participants (ICC = 0.91), with minimal contribution from technical differences. We demonstrate that multiparametric MRI is a non-invasive, repeatable and reproducible method for quantifying liver tissue characteristics across manufacturers (Philips and Siemens) and field strengths (1.5T and 3T).

The burden of liver disease continues to increase in the UK, with liver cirrhosis reported to be the third most common cause of premature death. Iron overload, a condition that impacts liver health, was traditionally associated with genetic disorders such as hereditary haemochromatosis, however, it is now increasingly associated with obesity, type-2 diabetes and non-alcoholic fatty liver disease. The aim of this study was to assess the prevalence of elevated levels of liver iron within the UK Biobank imaging study in a cohort of 9108 individuals. Magnetic resonance imaging (MRI) was undertaken at the UK Biobank imaging centre, acquiring a multi-echo spoiled gradient-echo single-breath-hold MRI sequence from the liver. All images were analysed for liver iron and fat (expressed as proton density fat fraction or PDFF) content using LiverMultiScan. Liver iron was measured in 97.3% of the cohort. The mean liver iron content was 1.32 ± 0.32 mg/g while the median was 1.25 mg/g (min: 0.85 max: 6.44 mg/g). Overall 4.82% of the population were defined as having elevated liver iron, above commonly accepted 1.8 mg/g threshold based on biochemical iron measurements in liver specimens obtained by biopsy. Further analysis using univariate models showed elevated liver iron to be related to male sex (p5.6% PDFF) was associated with a slight increase in prevalence of elevated liver iron (4.4% vs 6.3%, p = 0.0007). This study shows that population studies including measurement of liver iron concentration are feasible, which may in future be used to better inform patient stratification and treatment.

Non-invasive quantitation of liver disease using multiparametric magnetic resonance imaging (MRI) could refine clinical care pathways, trial design and preclinical drug development. The aim of this study was to evaluate the use of multiparametric MRI in experimental models of liver disease. Liver injury was induced in rats using 4 or 12 weeks of carbon tetrachloride (CCl4) intoxication and 4 or 8 weeks on a methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters [T1 mapping, T2* mapping and proton density fat fraction (PDFF)] were correlated with gold standard histopathological measures. Mean hepatic T1 increased significantly in rats treated with CCl4 for 12 weeks compared to controls [1122±78 ms versus 959±114 ms; d=162.7, 95% CI (11.92, 313.4), P=0.038] and correlated strongly with histological collagen content (rs=0.717, P=0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (rs=0.819, P, Summary: Multiparametric liver MRI was feasible in experimental rat models and imaging parameters correlated with gold standard histopathological assessments, especially characteristics of fatty liver disease.

PurposeSeveral studies have demonstrated the accuracy, precision, and reproducibility of proton density fat fraction (PDFF) quantification using vendor-specific image acquisition protocols and PDFF estimation methods. The purpose of this work is to validate a confounder-corrected, cross-vendor, cross field-strength, in-house variant LMS IDEAL of the IDEAL method licensed from the University of Wisconsin, which has been developed for routine clinical use.MethodsLMS IDEAL is implemented using a combination of patented and/or published acquisition and some novel model fitting methods required to correct confounds which result from the imaging and estimation processes, including: water-fat ambiguity; T2* relaxation; multi-peak fat modelling; main field inhomogeneity; T1 and noise bias; bipolar readout gradients; and eddy currents. LMS IDEAL has been designed to use image acquisition protocols that can be installed on most MRI scanners and cloud-based image processing to provide fast, standardized clinical results. Publicly available phantom data were used to validate LMS IDEAL PDFF calculations against results from originally published IDEAL methodology. LMS PDFF and T2* measurements were also compared with an independent technique in human volunteer data (n = 179) acquired as part of the UK Biobank study.ResultsWe demonstrate excellent agreement of LMS IDEAL across vendors, field strengths, and over a wide range of PDFF and T2* values in the phantom study. The performance of LMS IDEAL was then assessed in vivo against widely accepted PDFF and T2* estimation methods (LMS Dixon and LMS T2*, respectively), demonstrating the robustness of LMS IDEAL to potential sources of error.ConclusionThe development and clinical validation of the LMS IDEAL algorithm as a chemical shift-encoded MRI method for PDFF and T2* estimation contributes towards robust, unbiased applications for quantification of hepatic steatosis and iron overload, which are key features of chronic liver disease.

[This corrects the article DOI: 10.1371/journal.pone.0172921.].

Non-alcoholic fatty liver disease and the risk of progression to steatohepati tis, cirrhosis and hepatocellular carcinoma have been identified as major public health concerns. We have demonstrated the feasibility and potential value of measuring liver fat content by magnetic resonance imaging (MRI) in a large population in this study of 4,949 participants (aged 45– 73 years) in the UK Biobank imaging enhancement . Despite requirements for only a single ( 3min) scan of each subject, liver fat was able to be measured as the MRI proton density fat fraction (PDFF) with an overall success rate of 96.4%. The overall hepatic fat distribution was centred between 1–2%, and was highly skewed towards higher fat content. The mean PDFF was 3.91%, and median 2.11%. Analysis of PDFF in conjunction with other data fields available from the UK Biobank Resource showed associations of increased liver fat with greater age, BMI, weight gain, high blood pressure and Type 2 diabetes. Subjects with BMI less than 25 kg/m 2 had a low risk (5%) of high liver fat (PDFF > 5.5%), whereas in the higher BMI population ( > 30 kg/m 2 ) the prevalence of high liver fat was approximately 1 in 3. These data suggest that population screening to identify people with high PDFF is possible and could be cost effective. MRI based PDFF is an effective method for this. Finally, although cross sectional, this study suggests the utility of the PDFF measuremen t within UK Biobank, particularly for applications to elucidating risk factors through associations with prospec- tively acquired data on clinical outcomes of liver diseases, including non-alcoholic fatty liver disease.

A novel method for real-time magnetic resonance imaging for the assessment of cardiac function in mice at 9.4 T is proposed. The technique combines a highly undersampled radial gradient echo acquisition with an image reconstruction utilizing both parallel imaging and compressed sensing. Simulations on an in silico phantom were performed to determine the achievable acceleration factor and to optimize regularization parameters. Several parameters characterizing the quality of the reconstructed images (such as spatial and temporal image sharpness or compartment areas) were calculated for this purpose. Subsequently, double-gated segmented cine data as well as non-gated undersampled real-time data using only six projections per timeframe (temporal resolution $\sim 10~{\rm ms}$ ) were acquired in a mid-ventricular slice of four normal mouse hearts in vivo. The highly accelerated data sets were then subjected to the introduced reconstruction technique and results were validated against the fully sampled references. Functional parameters obtained from real-time and fully sampled data agreed well with a comparable accuracy for left-ventricular volumes and a slightly larger scatter for mass. This study introduces and validates a real-time cine-MRI technique, which significantly reduces scan time in preclinical cardiac functional imaging and has the potential to investigate mouse models with abnormal heart rhythm.

A fast version of the arterial spin tagging technique for the detection of cerebral perfusion is presented. Based on adiabatic spin inversion in combination with snapshot FLASH imaging our technique allows the recording of perfusion changes with a temporal resolution of about 3 s. Differences of cerebral perfusion dependent on the choice of anesthesia were observed in rat brain. Furthermore, with this arterial spin tagging method we demonstrated perfusion increases in the somatosensory cortex of anaesthetized rats during forepaw stimulation. Comparison of the activated areas in the T 2 * -weighted BOLD images and the perfusion-weighted images showed good spatial correspondence, but the sensitivity to the functional activation was more than ten times higher in the perfusion technique.

Focal cerebral ischaemia was produced in 11 rats by permanent occlusion of the right middle cerebral artery (MCA) using a suture model modified to enable manipulation with the animals in situ in an NMR spectrometer. The development of the ischaemic insults and the resultant infarcts were observed for up to 6 h by localized 1H MRS and diffusion-weighted MRI while performing continuous monitoring of electroencephalogram and extracellular DC potential. The ischaemic areas were depicted as regions of hyperintensity in the diffusion-weighted images. Signals due to lactate became visible in the 1H spectra after MCA occlusion indicating the onset of anaerobic glycolysis. A depletion of N-acetylaspartate was seen in all animals post-occlusion. Transient or stepwise increases of lactate were observed to occur coincidentally with the events of spontaneous transient peri-infarct depolarization detected by the electrophysiological measurements. Expansion of the ischaemic area delineated in the diffusion-weighted images also accompanied peri-infarct depolarizations. These observations are consistent with transient peri-infarct depolarization playing a role in the growth of infarcts.

Experimental brain tumors produced in rats (n = 10) by stereotactic implantation of cells from the F98 anaplastic glioma clone into the right caudate nucleus were studied in vivo using localized proton NMR and in vitro using high-resolution proton NMR, bioluminescent imaging of lactate, ATP and glucose distributions, and fluorescent imaging of regional pH. In vivo spectra from normal brain contralateral to the tumor regions showed resonances assignable to N-acetyl aspartate (NAA), creatines, choline-containing compounds, myo-inositol, glutamate and glucose in a pattern similar to those obtained from normal anaesthetized rats. In vivo tumor spectra were characterized by the almost complete absence of NAA, a substantial reduction of total creatine and glucose, and an increase of cholines. Based on the in vitro spectra the increase of the myo-inositol signal observed in vivo was mainly attributed to glycine. Histological examination as well as bioluminescent and fluorescent imaging indicated two stages of tumor development, i.e., solid vital tumors and tumors with necrosis. However, there was no consistent relationship between proton NMR observations and tumor development.

Localized proton NMR spectroscopy in vivo allows focal studies of cerebral metabolites in both man and laboratory animals from image-defined regions as small as 1 mL or 64 microL, respectively. Although brain tumours lead to remarkable spectral alterations relative to normal brain, a number of problems may compromise the interpretation of the results. Potential complications arise from the chosen experimental conditions (method, TE, size and location of volume of interest), from regional metabolic heterogeneity in and around tumours, from differences between human tumours and animal models, and from discrepancies between in vivo and in vitro findings. Strategies and pitfalls are illustrated with use of selected examples from primary brain tumours, a rat tumour model and perchloric acid extracts of resected specimens.

This paper describes a new method for diffusion imaging of the human brain in vivo that is based on a combination of diffusion-encoding gradients with high-speed STEAM MR imaging. The single-shot sequence 90 degrees-TE/2-90 degrees-TM-(alpha-TE/2-STE)n generates n = 32-64 differently phase-encoded stimulated echoes STE yielding image acquisition times of 576 ms for a 48 x 128 data matrix. Diffusion encoding is performed during the first TE/2-interval as well as during each readout period. Phantom studies reveal a quantitative agreement of calculated diffusion coefficients with literature values. EKG triggering completely eliminates motion artifacts from diffusion-weighted single-shot STEAM images of human brain in vivo. While signal attenuation of the cerebrospinal fluid (CSF) is predominantly due to flow, that observed for gray and white matter results from diffusion. Evaluated diffusion coefficients yield (1.0 +/- 0.1) x 10(-5) cm2 s-1 for gray matter, (0.5 +/- 0.1) x 10(-5) cm2 s-1 for white matter with the diffusion encoding parallel to the main orientation of the myelin sheath of the neurofibrils, and (0.3 +/- 0.1) x 10(-5) cm2 s-1 for white matter and a perpendicular orientation. All studies were performed at 2.0 T using a conventional 10 mT m-1 gradient system.

This contribution reports the first direct and noninvasive observation of cerebral glucose in normal anesthetized rats (n = 16) using short-echo-time localized proton NMR spectroscopy (2.35 T, STEAM, TR = 6000 ms, TE = 20 ms, 125 microliters). In addition to resonances from N-acetyl aspartate (NAA), glutamate, total creatine, cholines, taurine, and myoinositol, all spectra exhibit strongly coupled resonances from glucose (3.43, 3.80 ppm) that are readily identifiable using model solutions. The observed level of cerebral glucose in fasted rats covered a range of 15-40% of that of NAA giving absolute concentrations of 1.1-2.8 mM when NAA is taken to be 7 mM. The arterial blood glucose concentration was 7.7 +/- 0.8 mM in the same group of animals.

Cross-sectional magnetic resonance (MR) images of the normal hand, wrist, and fingers with an inplane resolution of 0.2-0.4 mm and a slice thickness of 1-2 mm were obtained using a 40-cm bore, 2.35-T MRI system equipped with actively shielded 50 mT m-1 gradient coils. A detailed description of the normal anatomy is given. The T1-weighted, multi-slice, fast low-angle shot (FLASH) MR images presented show a substantial improvement in resolution as compared with earlier reports. Typical investigational times of about 15 min offer a fast scan protocol that is suitable for routine clinical applications. The study further demonstrates the potential of dedicated magnets to facilitate and refine diagnostic MR imaging of hand injuries and hand-related diseases.

Localized 1H NMR spectra of human brain in vivo are affected by signal overlap, strong spin-spin coupling, and complex J modulation, and therefore differ considerably from those obtained at higher magnetic fields. This paper deals with the assignment of 1H NMR resonances of cerebral metabolites under the experimental conditions used for human investigations. Conventional 7.0-T FID spectra and 2.0 T localized, short echo time STEAM spectra (TE = 20 ms) of aqueous metabolite solutions are compared to in vivo brain spectra of human volunteers and patients. In addition to singlet resonances from N-acetyl aspartate (NAA), creatines, and cholines, short echo time STEAM spectra exhibit multiplets due to the NAA aspartyl group, glutamate, taurine, and myo-inositol. Enhanced levels of cerebral glutamine are detected in patients with liver cirrhosis. For the first time elevated levels of brain glucose are observed in patients with diabetes mellitus.

Subsecond fast low‐angle shot (FLASH) magnetic resonance imaging(MRI) allows single shot studies of the human heart within measuring times of about 100–300 ms depending on the data matrix. In contrast to conventional FLASH MRI subsecond applications acquire data d u r i n g the approach to steady state. A detailed analysis of the saturation behavior of the signal is given for the ideal case of a rectangular slice profile. In a second step, realistic slice profiles assuming Gaussian‐shaped excitation pulses were taken into account by means of a numerical solution of the Bloch equations. It turns out that the signal strength and the resulting image intensity is considerably higher than may be expected from steady‐state considerations. Correspondingly optimized flip angles depend on the number of phase‐encoding steps. Assuming long T 1relaxation times as, for example, encountered in muscle and brain tissue and repetition times of 5 ms or less, optimum flip angles are 12°–16°. The use of even higher flip angles (≥20°) causes heavily distorted slice profiles and a dynamic increase of the effective slice thickness. Flip angles of the order of the Ernst angle (6°) correspond to steady‐state conditions and lead to considerable signal losses. The theoretical results are confirmed by subsecond FLASH MRI studies of the human heart using a 2.0 T whole‐body system (Siemens Magnetom).

Phosphorus NMR spectroscopy of the brain of healthy volunteers (20–25 years) has been performed with use of the stimulated-echo (STEAM) localization technique. Investigations were carried out on a 2.0 T whole-body MRI/MRS system (Siemens Magnetom). Phosphorus spectra with echo times of TE ⩾ 3 ms were typically obtained in measuring times of about 10 min from a 125 ml volume-of-interest localized in the occipital part of the brain. The spectral resolution was optimized by localized shimming on the water proton signal (5–7 Hz) using the same sequence. Relaxation data were evaluated from spectra acquired under experimental conditions matched to the relaxation times of the individual metabolite resonances. Echo times ranged from 5 to 115 ms for T 2 determinations. For t 1 determinations repetition times were varied from 500 to 9000 ms. Broadband proton decoupling was achieved by means of a WALTZ-8 composite pulse sequence applied for the initial 68 ms of the 256 ms phosphorus acquisition period.

Flow-suppressed, subsecond FLASH MR images of the normal human heart have been obtained from single cardiac cycles using a 2.0-T whole-body MRI/MRS system (Siemens Magnetom) equipped with conventional 10 mT m-1 gradients. The present results demonstrate further technical improvements as compared to a previous report on the same subject (Magn. Reson. Med. 13:150-157; 1990). Measuring times of 139 msec and 209 msec were achieved by reducing the repetition time to TR = 4.36 msec (TE = 2.8 msec) and the spatial resolution to 32 x 128 or 48 x 128 measured data points, respectively. The flip angle was optimized to 12 degrees. Spatial pre-saturation of 60 mm thick sections adjacent to the imaging plane resulted in a suppression of the blood signal and a clear delineation of the myocardium. Oblique rotation of the imaging slice provides convenient access to the anatomical long axis and short axis views of the heart. EKG-triggered images from separate heartbeats but at different cardiac phases demonstrate that the effective time resolution is considerably less than the actual imaging time.

The effect of thrombolytic therapy was studied in rats submitted to thromboembolic stroke by intracarotid injection of autologous blood clots. Thrombolysis was initiated after 15 minutes with an intracarotid infusion of recombinant tissue-type activator (10 mg/kg body weight). Reperfusion was monitored for 3 hours using serial perfusion- and diffusion magnetic resonance imaging, and the outcome of treatment was quantified by pictorial measurements of ATP, tissue pH, and blood flow. In untreated animals, clot embolism resulted in an immediate decrease in blood flow and a sharp decrease in the apparent diffusion coefficient (ADC) that persisted throughout the observation period. Thrombolysis successfully recanalized the embolized middle cerebral artery origin and led to gradual improvement of blood flow and a slowly progressing reversal of ADC changes in the periphery of the ischemic territory, but only to transient and partial improvement in the center. Three hours after initiation of thrombolysis, the tissue volume with ADC values less than 80% of control was 39 ± 22% as compared to 61 ± 20% of ipsilateral hemisphere in untreated animals (means ± SD, P = .03) and the volume of ATP-depleted brain tissue was 25 ± 31% as compared to 46 ± 29% in untreated animals. Recovery of ischemic brain injury after thromboembolism is incomplete even when therapy is started as early as 15 minutes after clot embolism. Possible explanations for our findings include downstream displacement of clot material, microembolism of the vascular periphery, and events associated with reperfusion injury.

Functional activation of somatosensory cortex was studied in alpha-chloralose anesthetized rats by functional magnetic resonance imaging (fMRI), using both perfusion-weighted and T2*-weighted (blood oxygenation level dependent, BOLD) imaging. The sensitivity of functional activation was altered by ventilating animals for 3 minutes with 6% CO2. Before hypercapnic conditioning, electrical stimulation of the left forepaw at a frequency of 3 Hz led to an increase of signal intensity (relative to the unstimulated baseline condition) in the right somatosensory cortex by 6+/-2% (means+/-SD) in T2*-weighted images and by 45%+/-48% in perfusion-weighted images. After hypercapnic conditioning the signal intensity increase in perfusion-weighted images doubled to 91%+/-62% (P=0.034), whereas that of T2*-weighted images only marginally increased to 7+/-4% (not significant). This different behavior in both imaging modalities is interpreted as evidence for an increased flow response in combination with a higher oxygen extraction. Thus, the fMRI data reflect hypercapnia-induced resetting of the functional-metabolic coupling of the tissue during activation.

The effect of the novel inhibitor of receptor-activated and calcium store-operated nonselective cation channels, (RS)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-gamma 1)-2-phenyl-N, N-di-[2(2,3,4-trimethoxyphenyl) ethyl]acetamide (LOE 908 MS), on focal cerebral ischemia was studied in halothane-anesthetized rats submitted to permanent suture occlusion of the right middle cerebral artery (MCA). The treated group (n = 7) received subcutaneous injections of 30 mg/kg LOE 908 MS (in 1 ml saline) 10 min after vascular occlusion and again after 3 h. The untreated group (n = 11) was injected subcutaneously with 1 ml saline at the same times. Evolution of infarct was monitored by electrophysiological recording of EEG and cortical steady potential and by diffusion-weighted magnetic resonance imaging during the initial 6 h of vascular occlusion. The hemodynamic, biochemical, and morphological changes were studied after 6 h by combining autoradiographic measurement of blood flow with histological stainings and pictorial measurements of ATP, glucose, and tissue pH. In the untreated animals, the ischemic lesion volume [defined as the region in which the apparent diffusion coefficient (ADC) of water declined to below 80% of control] steadily increased by approximately 50% during the initial 6 h of vascular occlusion relative to the first set of data 10 min postocclusion. In the treated animals, in contrast, the ADC lesion volume declined by approximately 20% during the same interval. Treatment also led to a significant reduction in the number of periinfarct depolarizations. After 6 h of vascular occlusion, blood flow was significantly higher in the treated animals, and the volume of ATP-depleted and morphologically injured tissue representing the infarct core was 60-70% smaller. The volume of severely acidic tissue, in contrast, did not differ, indicating that LOE 908 MS does not reduce the size of ischemic penumbra. These findings demonstrate that postocclusion treatment of permanent focal ischemia with LOE 908 MS delays the expansion of the infarct core into the penumbra for a duration of at least 6 h and therefore substantially prolongs the window of opportunity for the reversal of the ischemic impact in the peripheral parts of the evolving infarct.

The NMR data in this study was interpreted statistically without using molecular and spectroscopical prior knowledge. Only the class origin (tumour/healthy tissue) was used as additional information for the training pattern. The samples were consistently classified successfully. This indicates that sample classification can be automated. Sensitivity analysis of the input pattern can be used for interpretation of NMR spectra without adding any medical or biochemical knowledge. The substances NAA, creatine, myo-inositol, choline and alanine were found to be important, the concentration of lactate seems to be an unreliable parameter for this classification problem. These results are exactly in line with clinical findings and medical interpretation of tumor metabolism. This study demonstrated, that NMR spectroscopy in combination with ANN offers a promising potential for the diagnosis of brain tumors.

The dependence of functional MRI contrast on the repetition rate (1.5-9 Hz) of a sensory stimulus was investigated with a T2*-weighted gradient echo method during forepaw stimulation of alpha-chloralose anesthetized rats (n = 5). An activation area was observed in the left or right somatosensory cortex dependent on the stimulation of the right or left forepaw, respectively. The activation intensity decreased for stimulation frequencies above 3 Hz, and was negligible at 9 Hz. The interpretation is that at low stimulation rates the neurons can respond to each stimulus, but at higher rates there is insufficient recovery time so that the response is progressively occluded.

Electrophysiological recording during in vivo NMR imaging for correlation of electrophysiological events with changes in NMR parameters has, until now, not been satisfactory. Here we present a method that uses specially prepared calomel electrodes for the continuous monitoring of both cortical steady potential and EEG during in vivo NMR imaging studies of experimental animal models. In order to demonstrate the reliability of this approach we elicited single episodes of cortical spreading depression in rats by intracortical potassium acetate injection, using an intracerebral micropipette. During the passage of DC potential shifts and associated reduction in EEG amplitude, hyperintense regions, reflecting the progression of cortical spreading depression over the cortex, were visible in diffusion-weighted images of the rat brains. No susceptibility artifacts due to the electrodes and micropipette were visible in the NMR data. Thus, we have demonstrated under controlled experimental conditions, that electrophysiological recording with calomel electrodes can be performed simultaneously with diffusion-weighted NMR imaging. The described method enables further NMR investigations of phenomena which are detectable by electrophysiology.

Focal cerebral ischemia causes rapid intensity changes in diffusion-weighted images (DWI) and elevated lactate as detected by localized proton spectroscopy (1H-MRS). To investigate whether such changes can also be evoked by perischemic depolarizations, we combined DWI and 1H-MRS measurements with DC potential recordings. About 40 min after occlusion of the middle cerebral artery in a rat, a negative DC deflection was observed indicating transient cell depolarization. Coincidentally with the depolarization a transient increase of the DWI signal intensity and a partially reversible increase of lactate occurred in the periphery of the ischemic territory. These results show that peri-ischemic depolarization, known to contribute to the evolution of cerebral infarction, evokes disturbances that can be detected by DWI and 1H-MRS.

F98 gliomas, E367 neuroblastomas, and RN6 Schwannomas in rat brain were studied non-invasively in vivo by localized proton MR spectroscopy (MRS). The spectra obtained from homotopic brain contralateral to the tumors were qualitatively indistinguishable from those of normal rat brain in vivo and showed resonance lines assigned to N-acetylaspartate, glutamate, total creatine (creatine and phosphocreatine), choline, glucose, and myo-inositol. The tumor spectra displayed marked differences compared to those obtained from contralateral brain. There were increases in choline, myo-inositol and lipids, which are presumably associated with increased membrane turnover. The presence of lactate indicated anaerobic glycolysis. Other differences included the absence of signals from NAA resulting from the destruction or displacement of neuronal tissue by the tumor. There was also a loss of total creatine. Although the spectra of all three tumor types were distinct from contralateral brain, there were no obvious differences between the different tumor types.

High-speed STEAM MR images of the normal human heart were obtained from single cardiac cycles using a 2.0-T whole-body system equipped with conventional 10 mT m-1 gradients. The single-shot 90 degrees-TE/2-90 degrees-TM-(alpha-TE/2-Acq)n pulse sequence acquires n differently phase-encoded stimulated echoes. Measuring times of 127-254 ms were achieved using a "repetition time" of 3.96 ms in conjunction with data matrices of 32-64 x 128 pixels covering a field-of-view of 250-350 mm. The sequence provides easy access to anatomical short-axis and long-axis views of the heart by single and double oblique rotation of the image orientation. STEAM images resemble the features of spin-echo images with respect to chemical shifts, susceptibilities, and flow. Thus, no additional techniques are required for the suppression of blood signals. EKG-triggered acquisitions demonstrate that slice-selective STEAM sequences using short TM intervals allow an unambiguous delineation of those parts of the myocardium that remain stationary within the selected plane throughout the entire imaging process. Neither spins leaving nor entering the slice defined by the initial 90 degrees RF pulses give rise to a stimulated echo and therefore do not contribute to the resulting image.

Fast scan MRI and image-guided localized proton spectroscopy were employed to assess both the morphology and the metabolic characteristics of brain lesions in a single investigation. Recent progress in the development of STEAM localization techniques allows the acquisition of proton MR spectra from volumes of interest as small as 1–8 ml within measuring times of 5–10 min. This enables the study of tumour heterogeneity to be done by proton spectroscopy, e.g. by monitoring variations in N-acetyl aspartate (NAA) and lactate levels between central necrosis and the surrounding portion of an astrocytoma. Metabolic alterations in small plaques of multiple sclerosis can also be studied without the results being compromised by partial volume effects. Typical findings include decreased levels of NAA and total creatine indicative of degeneration of the neuronal parenchyma, and increased choline consistent with membrano-proliferative gliosis.

Localized proton NMR spectroscopy using stimulated echoes (STEAM) has been used to study metabolites in different proximal skeletal muscles of normal volunteers at rest. Single scan water-suppressed proton NMR spectra obtained at 1.5 and 2.0 T (Siemens Magnetom) from a 64-ml volume-of-interest (VOI) yield resonances due to triglycerides, phosphocreatine plus a minor contribution from creatine, and betaines comprising carnitine and choline-containing compounds. The observation of the pH-dependent resonances of carnosine required multiple acquisitions and echo times as short as 20 ms. T1 and T2 relaxation times of muscle metabolites were obtained by varying the repetition time and echo time of the STEAM sequence, respectively. Although rather long T2 values such as 180 ms for (phospho-) creatine correspond to natural resonance linewidths of only 2 Hz, the observed linewidths of typically 10-12 Hz are entirely determined by the short T2 relaxation times (25-30 ms) of the water protons used for shimming. The spectroscopic results from 24 muscle studies on 17 young male volunteers show remarkable intra- and interindividual differences in the absolute signal intensities of mobile lipids. Further metabolic variations were observed for the relative concentrations of betaines (by a factor of 2) and carnosine (by a factor of 3) when total creatine is assumed to be constant.

Considerable technical improvements are reported for localized proton NMR spectroscopy using stimulated echoes. When compared to previous results, proton NMR spectra of the human brain are now obtainable (i) with in vivo water suppression factors of ⩾1000, (ii) with only minor T2 losses and negligible distortions due to J modulation at short echo times of 10–20 ms, and (iii) from volumes of interest as small as 1–8 ml within measuring times of 1–10 min. As a consequence, the detection of cerebral metabolites is greatly facilitated. This particularly applies to the assignment of those resonances (e.g., glutamate, taurine, inositols) that suffer from strong spin-spin coupling at the field strengths commonly in use for NMR in man. Studies of regional metabolite differences, tissue heterogeneity, and focal lesions in patients benefit from the increased spatial resolution and a concomitant reduction of partial volume effects. Localized proton NMR spectroscopy was performed on young healthy volunteers. Experiments were carried out on a 2.0 T whole-body MRI/MRS system using the standard headcoil for both imaging and spectroscopy.

Flow-suppressed FLASH MR images of the human heart have been recorded within a measuring time of 0.3 s using a 2.0-T whole-body research system (Siemens Magnetom) equipped with a conventional 10 mT m-1 gradient system. Subsecond imaging times have been achieved by reducing the repetition time to TR = 4.8 ms and by lowering the spatial resolution to 64 X 128 measured data points. The flip angle of the slice-selective radiofrequency (rf) pulses was adjusted to 10 degrees. Cardiac chambers, ventricular walls, and valves are well delineated in images from a single cardiac cycle using a field of 250 mm and a slice thickness of 8 mm. No motion artifacts were observed as a consequence of the short echo time of TE = 2.8 ms. Distinction between flowing blood and solid structures has been achieved by spatial presaturation of adjacent slices using two slice-selective 90 degrees rf pulses preceding the entire imaging sequence.

Severe motion and flow artifacts are a problem in MRI of diffusion in vivo due to the application of strong magnetic field gradients. Here it is shown that image artifacts can be removed by using a modified fast-scan MRI sequence (CE-FAST) in conjunction with averaging of diffusion-weighted images. In phantom studies slow (coherent) flow (

This paper describes a new fast scan technique for magnetic resonance imaging of molecular self-diffusion. The method is based on a modified CE-FAST nuclear magnetic resonance sequence acquiring echo coherences of the steady-state free precession (SSFP) signal. The incorporation of an additional magnetic field gradient pulse into each repetition interval of the CE-FAST sequence results in an attenuation of the echo part of the SSFP signal due to diffusion. The extent of diffusion weighting may be varied by changing the duration or strength of the gradient pulse as well as the diffusion time here given by the repetition time. A series of diffusion-weighted images allows the calculation of local diffusion coefficients. 1H NMR imaging experiments on phantoms have been carried out using a 40 cm bore 2.35 T Bruker system.

In the steady-state free precession sequence a regular sequence of phase-coherent radio-frequency pulses is applied with a repetition time shorter than the NMR relaxation times of the sample under investigation. The intensity of the resulting NMR signal has a complicated dependence on sequence repetition time and RF pulse angle, as well as dependence on the relaxation times. The purpose of this paper is to present a simple mathematical description of the SSFP NMR signals which may be used to accurately model SSFP experiments. Experimental verification of the model has been carried out on a 40 cm bore 2.35 T Bruker Medspec system.

A recently developed method for image-selected localized hydrogen-1 magnetic resonance (MR) spectroscopy was assessed in the differential diagnosis of nine primary and secondary cerebral tumors, including four gliomas, two meningiomas, one neurilemoma, one arachnoid cyst, and one metastasis of breast cancer. Well-resolved H-1 MR spectra of these tumors were obtained in vivo with a conventional 1.5-T whole-body MR imaging system. All tumor spectra were remarkably different from spectra from normal brain tissue. Spectra obtained from different tumors exhibited reproducible differences, while histologically similar tumors yielded characteristic spectra with only minor differences. The observed spectral alterations reflect variations in concentrations and relaxation times of the H-1 MR sensitive pool of free (mobile) metabolites within the tissues. In most cases, the concentrations of N-acetyl-aspartate and creatine/phosphocreatine are reduced below detectability, whereas choline-containing compounds are generally enhanced. The spectral differences between the tumors are mainly due to the differing concentrations of lipids, lactic acid, and carbohydrates. Localized H-1 MR spectroscopy may become an important clinical tool for the differentiation of tumors as well as for therapeutic control.

Water-suppressed localized proton NMR spectroscopy using stimulated echoes has been successfully applied to detect metabolites in the human brain in vivo. The STEAM spectroscopy sequence allows single-step localization by exciting three intersecting slices. Water suppression is achieved by preceding chemical-shift-selective (CHESS) rf pulses. High-resolution (0.05 ppm) proton NMR spectra of healthy volunteers have been High-resolution (0.05 ppm) proton NMR spectra of healthy volunteers have been obtained on a conventional 1.5-T whole-body MRI system (Siemens Magnetom). Volumes-of-interest (VOI) of 64 ml (4 x 4 x 4 cm3) were localized in the occipital area of the brain and spectra were recorded within measuring times ranging from 1 s (single scan) to about 10 min. The experimental procedure is described in detail. Resonance assignments include acetate, N-acetyl aspartate, gamma-amino butyrate, glutamine, glutamate, aspartate, creatine and phosphocreatine, choline-containing compounds, taurine, and inositols. Cerebral lactate was found to be at a maximum concentration of 0.5 mM when assuming N-acetyl aspartate in white matter to be 6 mM.

This paper describes a new technique for NMR angiography based on rapid line scan projection imaging and presaturation of stationary spins. The resulting line Scan angiograms are free from both misregistration artifacts common to subtraction methods and motion artifacts encountered in Fourier imaging. Moreover, line scan angiograms may be recorded within seconds and offer arbitrary fields of view as well as gradient zooming without problems due to aliasing. Three-dimensional information is obtained by rotation of the read gradient axis generating multiple view angles. Experimental line scan angiograms of the forearms of healthy volunteers have been recorded using a Bruker 2.35-T 40-cm magnet. © 1988 Academic Press, Inc.

“Diffusion-weighted” MRI in the normal human brain and in a patient with a cerebral metastasis is demonstrated. The method employed was a modified CE-FAST sequence with imaging times of only 6-10 s using a conventional 1.5-T whole-body MRI system (Siemens Magnetom). As with previous phantom and animal studies, the use of strong gradients together with macroscopic motions in vivo causes unavoidable artifacts in diffusion-weighted images of the human brain. While these artifacts are shown to be considerably reduced by averaging of 8-16 images, the resulting diffusion contrast is compromised by unknown signal losses due to motion. © 1989 Academic press, Inc.

Metabolites in brain and muscle of normal human volunteers have been studied by localized 1H and 31P NMR spectroscopy in vivo. Localization was achieved by means of stimulated echo (STEAM) sequences for both water-suppressed 1H NMR (TE = 20 ms) and 31P NMR (TE = 3 ms). Volumes-of-interest and measuring times selected for brain spectroscopy were 8 mL and 6.5 min for 1H NMR and 125 mL and 13 min for 31P NMR, respectively. General problems relating to spatial localization, spectral resolution, and quantitation of in vivo NMR data are discussed with respect to the nucleus and organs under investigation. They are correlated to studies of tissue extracts obtained at field strengths of 2.35 T (Bruker Biospec) and 7.0 T (Bruker MSL 300). Human studies were performed at 2.0 T on a whole-body research system (Siemens Magnetom).

High-resolution proton NMR spectra of normal human brain in vivo have been obtained from selected 27- and 64-ml volumes-of-interest (VOI) localized in the insular area, the occipital area, the thalamus, and the cerebellum of normal volunteers. Localization was achieved by stimulated echo (STEAM) sequences using a conventional 1.5-T whole-body MRI system (Siemens Magnetom). The proton NMR spectra show resonances from lipids, lactate, acetate, N-acetylaspartate (NAA), gamma-aminobutyrate, glutamine, glutamate, aspartate, creatine and phosphocreatine, choline-containing compounds, taurine, and inositols. While T1 relaxation times of most of these metabolites were about 1100-1700 ms without significant regional differences, their T2 relaxation times varied between 100 and 500 ms. The longest T2 values of about (500 +/- 50) ms were observed for the methyl protons of NAA in the white matter of the occipital lobe compared to (320 +/- 30) ms in the other parts of the brain. No significant regional T2 differences were found for choline and creatine methyl resonances. The relative concentrations of NAA in gray and white matter were found to be 35% higher than those in the thalamus and cerebellum. Assuming a concentration of 10 mM for total creatine the resulting NAA concentrations of 13-18 mM are by a factor of 2-3 higher than previously reported using analytical techniques. Cerebral lactate reached a maximum concentration of about 1.0 mM.

A multi-pulse radio frequency signal sequence includes a 90° excitation pulse (50) and at least a first 180° refocusing pulse (52) and a second 180° refocusing pulse (54). The excitation pulse and first refocusing pulse are separated by a duration A and the first and second refocusing pulses are separated by A+B. A free induction decay (60) follows the excitation pulse, a first spin echo (62) occurs a duration A after the first refocusing pulse and a second spin echo (64) occurs the duration B after the second refocusing pulse. A first read gradient (90) is applied between the excitation and first refocusing pulses; a second read gradient (92) is applied between the first refocusing pulse and the first spin echo; a third read gradient (94) is applied between the first spin echo and the second refocusing pulse; and a fourth read gradient (96) is applied between the second refocusing pulse and the second spin echo. Because the 90° and 180° pulses are imperfect, parasitic echoes occur at durations 3A+B, 3A+2B, and 4A+2B after the 90° excitation pulse. To avoid contamination of the spin echo data by the parasitic echoes, the durations A and B are selected such that the parasitic echoes are each displaced from the spin echoes. To shift the parasitic echoes into times which are non-coincident with the spin echoes, the amplitudes of the read gradients are similarly varied between the spin echoes to shift the parasitic echoes relative to the spin echoes.