Showing papers in "NMR in Biomedicine in 2001"

Automatic quantitation of localized in vivo 1H spectra with LCModel

Abstract: The LCModel method analyzes an in vivo spectrum as a Linear Combination of Model in vitro spectra from individual metabolite solutions. Complete model spectra, rather than individual resonances, are used in order to incorporate maximum prior information into the analysis. A nearly model-free constrained regularization method automatically accounts for the baseline and lineshape in vivo without imposing a restrictive parameterized form on them. LCModel is automatic (non-interactive) with no subjective input. Approximately maximum-likelihood estimates of the metabolite concentrations and their uncertainties (Cramer-Rao lower bounds) are obtained. LCModel analyses of spectra from users with fields from 1.5 to 9.4 T and a wide range of sequences, particularly with short TE, are used here to illustrate the capabilities and limitations of LCModel and proton MRS.

Magnetization transfer in MRI: a review.

Abstract: This review describes magnetization transfer (MT) contrast in magnetic resonance imaging. A qualitative description of how MT works is provided along with experimental evidence that leads to a quantitative model for MT in tissues. The implementation of MT saturation in imaging sequences and the interpretation of the MT-induced signal change in terms of exchange processes and direct effects are presented. Finally, highlights of clinical uses of MT are outlined and future directions for investigation proposed.

Cramér–Rao bounds: an evaluation tool for quantitation

Abstract: The Cramer-Rao lower bounds (CRBs) are the lowest possible standard deviations of all unbiased model parameter estimates obtained from the data. Consequently they give insight into the potential performance of quantitation estimators. Using analytical CRB expressions for spectral parameters of singlets and doublets in noise, one is able to judge the precision as a function of spectral and experimental parameters. We point out the usefulness of these expressions for experimental design. The influence of constraints (chemical prior knowledge) on spectral parameters of the peaks of doublets is demonstrated and the inherent benefits for quantitation are shown. Abbreviations used: CRB Cramer-Rao lower bounds

Proton T (1) and T (2) relaxation times of human brain metabolites at 3 Tesla.

Abstract: Methods Ten relaxation measurements were done with the VOIs localised in the occipital gray (GM) or white (WM) matter. Experiments were performed on a 3 T Bruker MEDSPEC system using a 10 cm planar surface coil as a transmitter/receiver. A VOI of 2´2´2 cm3 was selected in the brain of healthy subjects using the STEAM sequence with TR = 6sa nd TM =6 0 ms.B1 insensitive water suppression was achieved by a modified SWAMP method (2,3). For determining T1 values, an inversion recovery technique was used with an additional 30 ms hyperbolic secant full passage pulse (offset -250 Hz relative to the water resonance) preceding the localisation sequence. At least five inversion times (TI) were chosen in the range from 150 ms to 1650 ms. Equilibrium values of signal intensities were read from the spectra without inversion. The short echo time (TE) of 9 ms was used in most measurements, except for two series of spectra with TE of 50 ms in GM and WM, respectively. The T1 values were calculated from semilogarithmic plots of (Ieq-ITI )v ersus TI. TheT2 values were obtained from slopes of semilogarithmic plots of ITE versus TE using the spectra with TE from 50 to 250 ms. Results The calculated T1 relaxation times are summarized in Table 1. At short TI values, recovery of the creatine methylene peak at 3.92 ppm was faster while it slowed down for the longer TI values. When the measurement was performed with TE = 50 ms, the semilogarithmic plot of the data for the Cr(3.92) line was linear. The calculated T1 of about 900 ms matched well the short T1 component found in the experiments with TE = 9 ms. For measuring the T2 relaxation times, the spectra with TE = 9 ms could not be used for the calculations as they contained substantial amounts of the macromolecular components and/or J-coupled multiplets of the other metabolites. When TE >5 0 ms spectra were used in the calculation, linearity of the semilogarithmic fits was satisfactory. Our results and the previously published relevant data are shown in Table 2. Note the general trend of decreasing T2 relaxation times with increasing B0.

High-resolution BOLD venographic imaging: a window into brain function.

Abstract: This paper reviews the recent development of a new high-resolution magnetic resonance imaging approach to visualizing small veins in the human brain with diameters in the sub-millimeter range, which is smaller than a voxel. It briefly introduces the physical background of the underlying bulk magnetic susceptibility effects, on which this approach is based, and it demonstrates the successful application of the method for imaging different intracranial lesions, like venous anomalies, arteriovenous malformations and brain tumors. The susceptibility difference between venous blood and the surrounding tissue is used to generate contrast. Using this method it is possible to visualize draining veins in lesions better than conventional magnetic resonance imaging methods, which often require application of a contrast medium or even conventional catheter angiography. Limitations of the method are discussed. The ability to highlight deoxygenated blood with high spatial resolution yields important vascular parameters which may be helpful for improved modeling of MR signal changes during functional brain activation, it may lead to a better understanding of brain function in diseased states, or it may even offer the possibility of differentiating benign from malignant tumors non-invasively.

MR spectroscopy quantitation: a review of time‐domain methods

Abstract: In this article an overview of time-domain quantitation methods is given. Advantages of processing the data in the measurement domain are discussed. The basic underlying principles of the methods are outlined and from them the situations under which these algorithms perform well are derived. Also an overview of methods to preprocess the data is given. In that respect, signal-to-noise and/or resolution enhancement, the removal of unwanted components and corrections for model imperfections are discussed.

The effects of microscopic tissue parameters on the diffusion weighted magnetic resonance imaging experiment

Abstract: This review examines the way in which microscopic tissue parameters can affect MR experiments which are sensitive to diffusion. The interaction between the intra- and extravascular as well as that between the intra- and extracellular spaces is examined. Susceptibility gradients due to the presence of deoxyhemoglobin can cause diffusion-induced signal losses which are significant in functional magnetic resonance experiments, particularly at higher main magnetic field strengths. This is also true of the fast response that manifests itself as an early negative signal change in functional magnetic resonance experiments. The fields surrounding paramagnetic vessels are described and the way in which diffusion in these fields contributes to functional signal changes is examined. Flow in the capillary bed can be a confounding factor in experiments which aim to examine the diffusion characteristics of extravascular water. It is potentially also a method for assessing capillary perfusion. The intravoxel incoherent motion experiment is described in terms of how significantly this effect can influence diffusion attenuation curves from water. The major models for describing water diffusion in tissue are presented, as are the main experimental results that have contributed to an understanding of the mechanisms of diffusion contrast. The widely accepted view that changes in the diffusion characteristics are caused by a shift of water to the intracellular space and a concomitant change in extracellular tortuosity is examined critically. More recent experiments that indicate that a reduction in the intracellular diffusion may occur simultaneously with the cell swelling are described and their compatibility with existing models discussed. Copyright © 2001 John Wiley & Sons, Ltd. Abbreviations used: 2FDG-6P fluor-2-deoxyglucose-6-phosphate ADC apparent diffusion coefficient BOLD blood oxygen level dependent CNS central nervous system CSF cerebro spinal fluid DTI diffusion tensor imaging DWI diffusion weighted imaging fMR functional magnetic resonance FR fast response IVCM intravoxel coherent motion IVIM intravoxel incoherent motion MCAO middle cerebral artery occlusion MRI magnetic resonance imaging NMDA N-methyl-D-aspartate NMR nuclear magnetic resonance PFG pulsed field gradient rBF regional blood flow SGP short gradient pulse TE echo time.

MR spectroscopy quantitation: a review of frequency domain methods.

Abstract: There has been a vast increase in applications of magnetic resonance spectroscopy (MRS) in biomedical research during the last few years. This is not surprising since MRS provides both in vivo and in vitro a non-invasive tool for various biochemical and biomedical studies. There are also expectations that clinical MRS will have an important role as a diagnostic tool. An essential prerequisite for the future success of MRS for applicability in biomedical sciences will be accurate and biochemically relevant data analysis (at as high a level of automation as possible). This review briefly describes principles of the methodology available for advanced quantitative data analysis in the frequency domain. Various biomedical applications are discussed in order to illustrate the practical aspects of the analyses and to show the applicability and power of biochemical prior knowledge-based lineshape fitting analysis.

Quantitative functional imaging of the brain: towards mapping neuronal activity by BOLD fMRI.

Abstract: Quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS) measurements of energy metabolism (i.e. cerebral metabolic rate of oxygen consumption, CMRO2), blood circulation (i.e. cerebral blood flow, CBF, and volume, CBV), and functional MRI (fMRI) signal over a wide range of neuronal activity and pharmacological treatments are used to interpret the neurophysiologic basis of blood oxygenation level dependent (BOLD) image-contrast at 7 T in glutamatergic neurons of rat cerebral cortex. Multi-modal MRI and MRS measurements of CMRO2, CBF, CBV and BOLD signal (both gradient-echo and spin-echo) are used to interpret the neuroenergetic basis of BOLD image-contrast. Since each parameter that can influence the BOLD image-contrast is measured quantitatively and separately, multi-modal measurements of changes in CMRO2, CBF, CBV, BOLD fMRI signal allow calibration and validation of the BOLD image-contrast. Good agreement between changes in CMRO2 calculated from BOLD theory and measured by 13C MRS, reveals that BOLD fMRI signal-changes at 7 T are closely linked with alterations in neuronal glucose oxidation, both for activation and deactivation paradigms. To determine the neurochemical basis of BOLD, pharmacological treatment with lamotrigine, which is a neuronal voltage-dependent Na+ channel blocker and neurotransmitter glutamate release inhibitor, is used in a rat forepaw stimulation model. Attenuation of the functional changes in CBF and BOLD with lamotrigine reveals that the fMRI signal is associated with release of glutamate from neurons, which is consistent with a link between neurotransmitter cycling and energy metabolism. Comparisons of CMRO2 and CBF over a wide dynamic range of neuronal activity provide insight into the regulation of energy metabolism and oxygen delivery in the cerebral cortex. The current results reveal the energetic and physiologic components of the BOLD fMRI signal and indicate the required steps towards mapping neuronal activity quantitatively by fMRI at steady-state. Consequences of these results from rat brain for similar calibrated BOLD fMRI studies in the human brain are discussed. Copyright © 2001 John Wiley & Sons, Ltd.

Issues in flow and oxygenation dependent contrast (FLOOD) imaging of tumours.

Abstract: The sensitivity of blood oxygenation level dependent (BOLD) contrast techniques to changes to tumour deoxyhaemoglobin concentration is of relevance to many strategies in cancer treatments. In the context of tumour studies, which frequently involve the use of agents to modify blood flow, there are underlying physiological changes different to those of BOLD in the brain. Hence we use the term, flow and oxygenation dependent (FLOOD) contrast, to emphasize this difference and the importance of flow effects. We have measured the R2* changes in a prolactinoma tumour model for a variety of vasoactive challenges [carbogen, 100% oxygen and 100% nitrogen as different breathing gases, and administration of tumour blood flow modifiers such as calcitonin gene related peptide (CGRP), hydralazine and nicotinamide]. In addition we have measured other relevant physiological parameters, such as bioenergetic status from 31P MRS, and blood pH and glucose, that may change during a vasoactive challenge. Here we discuss how they relate to our understanding of FLOOD contrast in tumours. We frequently observe R2* changes that match the expected action of the vascular stimulus: R2* decreases with agents expected to improve tumour oxygenation and blood flow, and increases with agents designed to increase tumour hypoxia. Unlike most normal tissues, tumours have a chaotic and poorly regulated blood supply, and a mix of glycolytic and oxidative metabolism; thus the response to a vasoactive challenge is not predictable. Changes in blood volume can counteract the effect of blood oxygenation changes, and changes in blood pH and glucose levels can alter oxygen extraction. This can lead to R2* changes that are smaller or the reverse of those expected. To properly interpret FLOOD contrast changes these effects must be accounted for. Copyright © 2001 John Wiley & Sons, Ltd.

Diffusion NMR spectroscopy.

Abstract: MR offers unique tools for measuring molecular diffusion. This review focuses on the use of diffusion-weighted MR spectroscopy (DW-MRS) to non-invasively quantitate the translational displacement of endogenous metabolites in intact mammalian tissues. Most of the metabolites that are observed by in vivo MRS are predominantly located in the intracellular compartment. DW-MRS is of fundamental interest because it enables one to probe the in situ status of the intracellular space from the diffusion characteristics of the metabolites, while at the same time providing information on the intrinsic diffusion properties of the metabolites themselves. Alternative techniques require the introduction of exogenous probe molecules, which involves invasive procedures, and are also unable to measure molecular diffusion in and throughout intact tissues. The length scale of the process(es) probed by MR is in the micrometer range which is of the same order as the dimensions of many intracellular entities. DW-MRS has been used to estimate the dimensions of the cellular elements that restrict intracellular metabolite diffusion in muscle and nerve tissue. In addition, it has been shown that DW-MRS can provide novel information on the cellular response to pathophysiological changes in relation to a range of disorders, including ischemia and excitotoxicity of the brain and cancer.

Multiquantum filters and order in tissues.

Abstract: In ordered systems, where the molecular motion is anisotropic, quadrupolar and dipolar interactions are not averaged to zero. In such cases, double quantum (DQ) coherences can be formed. This review deals mainly with the effect of anisotropic motion of water molecules and sodium ions in intact biological tissues on (2)H, (1)H and (23)Na NMR spectroscopy and its application to NMR imaging (MRI). Double quantum filtered (DQF) spectra of water molecules and sodium ions were detected in a variety of ordered biological tissues. In collagen-containing tissues such as ligaments, tendons, cartilage, skin, blood vessels and nerves, the DQ coherences are formed as a result of the interaction with the collagen fibers. In red blood cells and presumably also in nerve axons it stems from the interaction with the cytoskeleton. For (23)Na, an I = 3/2 nucleus, the DQ coherences can also be formed in isotropic media. By a judicial choice of the pulse angle in the DQ pulse sequence only the DQ coherences arising from anisotropic motion are detected. For I = 1 nuclei such as 2H, DQF spectra can be observed only in ordered structures. Thus, the observation of 2H DQF spectra is an indication of order. The same is true for pairs of equivalent 1H nuclei. The dependence of the DQF signal on the creation time of the double quantum coherences is characteristic to each tissue and allows signals to be resolved from different tissues by performing the measurements at different creation times. In this way, the 2H DQF signals of the different compartments of sciatic nerve were resolved and water diffusion in each compartment was studied independently. In the axon, the diffusion was heavily restricted perpendicular to the axon's long axis, a result from which the axon diameter could be deduced. In blood vessel walls, this characteristic enabled the different layers of the vessel to be viewed and studied under strain. For 2H, a DQF spectroscopic imaging sequence was used to study the orientation of the collagen fibers in the different zones of articular cartilage and bone plug. The effect of pressure on the fibers and their return to equilibrium was studied as well. In blood vessels, a DQF image was obtained and strain maps of the different layers were calculated. The efficiency of the 1H DQF imaging technique was demonstrated on a phantom of rat tail where only the four tendons were detected at short creation times. 1H DQF imaging and spectroscopy followed the healing of a rabbit's ruptured Achilles tendon and the results were far more sensitive to the process than conventional imaging. Finally, the method was implemented on a commercial whole body MRI spectrometer. Images of human wrist and ankle showed a positive contrast for the tendons and ligaments, indicating the potential of the method for clinical imaging. (c) 2001 John Wiley & Sons, Ltd.

Investigation of the initial dip in fMRI at 7 Tesla.

Abstract: In agreement with optical imaging studies, previous fMRI studies have reported an initial decrease (i.e. the initial dip) in the BOLD response, which is believed to arise from an increase in oxygen consumption and to be mostly microvascular. To date, experimental studies of the initial dip in humans have been performed at fields up to 4 T, with relatively low spatial resolution. Because the sensitivity to microvascular contribution is increased at high magnetic fields, the present study investigated the initial dip at 7 T. In addition, to reduce the partial volume effect, the study is conducted at a high spatial resolution. The initial dip was detected in all subjects studied and was found to reside mostly in the gray matter. The relative amplitude of the early response was found to be 0.6, higher than that at 4 T (0.3) and 1.5 T (0.11). In addition, based on the assumption that the initial dip is a result of increased oxygen utilization, the fractional change in oxygen utilization was estimated to be 40% of that of the fractional change in cerebral blood flow. These results are in agreement with the notion that the initial dip arises from an increase in oxygen consumption.

Lactate efflux and the neuroenergetic basis of brain function.

Abstract: In the unstimulated brain energy is primarily supplied by the oxidation of glucose. However the oxygen-to-glucose index (OGI), which is the ratio of metabolic rates of oxygen to glucose, CMR(O2)/CMR(glc), diverges from the theoretical value of 6 as activity is increased. In vivo measurements of brain lactate show its concentration to increase with stimulation. The decreasing OGI with stimulation had led to the suggestion that activation, unlike resting activity, is supported by anaerobic glycolysis. To date a unifying concept that accommodates glucose oxidation at rest with lactate generation and OGI decrease during stimulation of brain is lacking. Furthermore, energetics that change with increasing activity are not consistent with a neuroenergetic model that has been proposed from 1-(13)C-glucose MRS experiments. That model, based upon in vivo MRS measurements and cellular studies by Pellerin and Magistretti, showed that glutamate neurotransmitter cycling was coupled to glucose oxidation over a wide range of brain activities from rest down to deep anesthesia. Here we reconcile these paradoxical observations by suggesting that anaerobic glucose consumption (which can provide energy rapidly) increases with activation to meet the power requirements of millisecond neuronal firing. It is proposed, in accord with our neuroenergetic model, that the extra glucose mobilized rapidly for glial clearance of glutamate, is not needed for the oxidative processes that are responsible for neuronal firing and glutamate release, and consequently it is effluxed as lactate. A stoichiometric relation between OGI and lactate concentration is derived from the neuroenergetic model, showing that the enhanced glucose uptake during activation is consistent with neuronal activity being energetically supported by glucose oxidation.

Detection of BOLD changes by means of a frequency-sensitive trueFISP technique : preliminary results

Abstract: A new method is introduced to detect magnetic field modulation arising from brain activation-induced BOLD effects. This approach uses a two-dimensional high-bandwidth, high-resolution conventional gradient-echo steady-state imaging sequence known as TrueFISP. The ability to visualize changes in oxygen saturation comes from the fact that the method is sensitive to the local field. As is well known, as the oxygen saturation changes so does the local field associated with the venous blood. We demonstrate that it is possible to visualize not only venous blood with this approach on a macroscopic level for major veins, but also to measure conventional oscillatory like signal changes during activated and resting states. Unfortunately, the method has two major drawbacks. First, a long TR is needed to maximize signal changes and, second, the field must be very well shimmed or numerous experiments need to be run to find the activation, as the signal response is sensitive to the starting frequency in the resting state. Nevertheless, these images can be compared directly with anatomical images collected with the same method without the need for distortion correction.

1H‐ and 31P‐MR spectroscopy of primary and recurrent human brain tumors in vitro: malignancy‐characteristic profiles of water soluble and lipophilic spectral components

Abstract: In vitro NMR spectrocopy was performed on specimen of human brain tumors. From all patients, tissue samples of primary tumors and their first recurrences were examined. 31P- and 1H-spectra were recorded from samples of meningioma, astrocytoma and glioblastoma. A double extraction procedure of the tissue samples permitted acquisition of information from the membrane fraction and from the cytosolic fraction. 31P-spectra were used to analyze the lipophilic fraction (phospholipids of the membrane) of the tissue extracts, while the 1H-spectra reflected information on the metabolic alterations of the hydrophilic, cytosolic fraction of the tissue. The tumor types showed distinctive spectral patterns in both the 31P- and the 1H-spectra. Based on the total detectable 31P signal, the level of phosphatidylcholine was about 34% lower in primary astrocytomas than in primary glioblastomas (p = 0.0003), whereas the level of sphingomyelin was about 45% lower in primary gioblastomas than in primary astrocytomas (p = 0.0061). A similar tendency of these phospholipids was observed when comparing primary and recurrent astrocytoma samples from the same individuals [+15% (p = 0.0103) and −23% (p = 0.0314) change, respectively]. 1H-spectra of gliomas were characterized by an increase of the ratios of alanine, glycine and choline over creatine as a function of the degree of malignancy. In agreement with findings in the 31P-spectra, the 1H-spectra of recurrent astrocytomas showed metabolic profiles of increased malignancy in comparison to their primary occurrence. Since gliomas tend to increase in malignancy upon recurrence, this may reflect evolving tumor metabolism. 1H-spectra of meningiomas showed the highest ratio of alanine over creatine accompanied by a near absence of myo-inositol. Phospholipid profiles of meningiomas showed higher fractional contents of phosphatidylcholine along with lower phosphatidylserine compared to astrocytomas, while higher phosphatidylethanolamine and sphingomyelin fractional contents distinguished meningiomas from glioblastomas. The extraction method being used in this study combined with high-resolution 1H- and 31P-MRS provides a wide range of biochemical information, which enables differentiation not only between tumor types but also between primary and recurrent gliomas, reflecting an evolving tumor metabolism. Copyright © 2001 John Wiley & Sons, Ltd.

NMR spectral quantitation by principal component analysis

Abstract: The use of principal component analysis (PCA) for simultaneous spectral quantitation of a single resonant peak across a series of spectra has gained popularity among the NMR community. The approach is fast, requires no assumptions regarding the peak lineshape and provides quantitation even for peaks with very low signal-to-noise ratio. PCA produces estimates of all peak parameters: area, frequency, phase and linewidth. If desired, these estimates can be used to correct the original data so that the peak in all spectra has the same lineshape. This ability makes PCA useful not only for direct peak quantitation, but also for processing spectral data prior to application of pattern recognition/classification techniques. This article briefly reviews the theoretical basis of PCA for spectral quantitation, addresses issues of data processing prior to PCA, describes suitable and unsuitable datasets for PCA applications and summarizes the developments and the limitations of the method.

In vivo single-voxel proton MR spectroscopy in brain lesions with ring-like enhancement

Abstract: It is often difficult to make a correct diagnosis of ring-like enhanced lesions on Gd-enhanced MR brain images. To differentiate these lesions using proton MR spectroscopy (1H-MRS), we retrospectively evaluated the correlation between the 1H-MR spectra and histopathological findings. We evaluated proton MR spectra obtained from the lesions in 45 patients, including metastasis (n = 19), glioblastoma (n = 10), radiation necrosis (n = 7), brain abscess (n = 5), and cerebral infarction (n = 4). The rate of misdiagnosis was found to be lowest at the threshold level of 2.48 for the (choline containing compounds)/(creatine and phosphocreatine) ratio (Cho/Cr) obtained from the whole lesions, which include the enhanced rim and the non-enhanced inner region. That is, the positively predictive values of a Cho/Cr greater than 2.48 for diagnosing metastasis or glioblastoma was 88.9 and 60.0%, respectively, and the positively predictive value of a Cho/Cr less than 2.48 for diagnosing radiation necrosis or cerebral infarction was 71.4 and 100%, respectively. For further differentiating between metastasis and glioblastoma, information about the presence and absence of an N-acetyl-aspartate (NAA) peak and lipid- or lactate-dominant peak was found to be useful. In 73.7% of metastasis cases a lipid-dominant peak was observed in the whole lesion without an NAA peak in the inner region, whereas the same pattern was observed in only 10% of the glioblastoma cases. Correlation with the histopathological findings showed that a high Cho signal is suggestive of neoplasm. Lipid signal in the non-enhanced central region was correlated to necrosis. Lactate signals were often observed in glioblastoma, abscess and sometimes metastasis, presumably reflecting the anaerobic glycolysis by the living cells in the ring-like enhanced rim. Single-voxel proton MR spectroscopy may serve as a potential tool to provide useful information of differentiation of ring-like enhanced lesions that cannot be diagnosed correctly using enhanced MR images alone.

Magnetization transfer MRS

Abstract: This review deals with magnetization transfer (MT) effects observed in in vivo NMR spectroscopy. The basic experimental methods of MT experiments, the underlying kinetic mechanisms as well as the evaluation of measured data by fits to two- or three-pool models are described. Experimental results of both (31)P and (1)H in vivo MRS are reviewed showing the potential of MT experiments to characterize kinetic equilibrium reactions. This includes reactions where all involved components are MR visible, as well as situations where one indirectly measures pools of bound spins which cannot directly be observed in vivo. In particular, MT effects are described which have been observed in in vivo (1)H NMR spectra measured on the animal or human brain or on skeletal muscle. Possible mechanisms for the strong MT effects observed for the signals of creatine/phosphocreatine, lactate, alcohol and other metabolites are discussed. It is also emphasized that MT effects caused by water suppression techniques may lead to systematic errors in the quantification of in vivo (1)H NMR spectra.

Dipolar coupling and ordering effects observed in magnetic resonance spectra of skeletal muscle

Abstract: Skeletal muscle is a biological structure with a high degree of organization at different spatial levels. This order influences magnetic resonance (MR) in vivo-in particular 1H-spectra-by a series of effects that have very distinct physical sources and biomedical applications: (a) bulk fat (extramyocellular lipids, EMCL) along fasciae forms macroscopic plates, changing the susceptibility within these structures compared to the spherical droplets that contain intra-myocellular lipids (IMCL); this effect leads to a separation of the signals from EMCL and IMCL; (b) dipolar coupling effects due to anisotropic motional averaging have been shown for 1H-resonances of creatine, taurine, and lactate; (c) aromatic protons of carnosine show orientation-dependent effects that can be explained by dipolar coupling, chemical shift anisotropy or by relaxation anisotropy; (d) limited rotational freedom and/or compartmentation may explain differences of 1H-MR-visibility of the creatine/phosphocreatine resonances; (e) lactate 1H-MR resonances are reported to reveal information on tissue compartmentation; (f) transverse relaxation of water and metabolites show multiple components, indicative of intra-, extracellular and/or macromolecular-bound pools, and in addition dipolar or J-coupling lead to a modulation of the signal decay, hindering straightforward interpretation; (g) diffusion weighted 31P-MRS has shown restricted diffusion of phosphocreatine; (h) magnetization transfer (MT) indicates that there is a motionally restricted proton pool in spin-exchange with free creatine; reduced availability or restricted motion of creatine is particularly important for an estimation of ADP from 31P-MR spectra, and in addition MT effects may alter the signal intensity of creatine 1H-resonances following water-suppression pulses; (i) transcytolemmal water-exchange can be studied in 1H-MRS by contrast-agents applied to the extracellular space; (k) transport of glucose across the cell membrane has been studied in diabetes patients using a combination of 13C- and 31P-MRS; and l residual quadrupolar interaction in 23Na MR spectra from human skeletal muscle suggest that sodium ions are bound to ordered muscular structures.

1‐13C glucose magnetic resonance spectroscopy of pediatric and adult brain disorders

Abstract: With protocols designed for use in a clinical environment we investigated the feasibility and diagnostic potential of (13)C MRS after 1-(13)C labeled glucose infusion. (13)C MRS brain examinations were performed in 27 subjects (17 children and pediatric patients, six adult patients, and four adult controls), using a standard 1.5 T clinical MR scanner. 1-(13)C glucose, 99% enriched (20% w/v) was administered intravenously (690 or 210 mg/kg body weight) or orally (730 mg/kg). Cerebral (13)C-enrichment patterns and time courses were compared. 1-(13)C glucose appeared in brain spectra within 2.5-15 min, with ensuing enrichment of its metabolites. No complications were encountered. When data obtained in patients were compared with controls, striking abnormalities in hepatic encephalopathy and in premature brain were observed, consistent with reduced cerebral glucose metabolism. Abnormalities in the (13)C enrichment pattern were also observed in pediatric patients with leukodystrophies and mitochondrial disorders. In this preliminary survey, we conclude that (13)C MRS in combination with glucose infusion is safe and efficient and provides new insights into the pathophysiology of brain disorders.

Common processing of in vivo MR spectra

Abstract: This introductory article addresses approaches currently in use to process in vivo spectra. First, a brief overview is given of the information content represented by the parameters of MR signals. Subsequently, common steps in the processing of MR spectra such as pre-processing, normalisation and quantification and the use of prior knowledge are described. Finally, some prospects for more advanced processing are given.

MRI of lung parenchyma in rats and mice using a gradient-echo sequence.

Abstract: Signal of lung parenchymal tissue from the living rat and mouse lung was detected at 4.7 T with a good signal-to-noise ratio and motion-suppressed artifacts using a short TE gradient-echo sequence. Neither cardiac nor respiratory gating were applied, and animals respired freely during data collection. Mean T(2)* relaxation times of parenchyma in the anterior, middle and posterior regions of both lungs ranged between 403 and 657 micros and 397 and 751 micros, respectively for the rat and mouse. For the rat in the prone position, there was a gradient in T(2)* values, from the posterior to the anterior regions of both lungs. In the supine position, however, T(2)* values were larger in the posterior and in the anterior portions. For the mouse in both prone and supine positions, there was a tendential gradient in T(2)* from the anterior to the posterior portions. The robustness of the approach renders it well suited for routine applications, e.g. in pharmacological studies concerning asthma models in small rodents. The method was applied to lung inflammation models involving challenge with ovalbumin or lipopolysaccharide.

Relaxation times and microstructures.

Abstract: A discussion is presented of the evaluation of multiple relaxation components from water protons in biological tissue. The principal focus is to draw attention to the way in which limitations in the raw NMR data, such as signal-to-noise ratio, data sampling density and acquisition window width, affect the precision and resolution in the processed multiple component solution of the return to thermal equilibrium. The second issue discussed is the interpretation of these multiple components in terms of microstructural compartments of the biological sample and, thirdly, we outline some of the successes in determining regional and pathological variations in microstructure in the human body in-vivo, using the technique of multiple relaxation components.

Quantitative measurements of cerebral metabolic rate of oxygen utilization using MRI: a volunteer study

Abstract: Quantitative estimates of cerebral metabolic rate of oxygen utilization using magnetic resonance imaging can have profound implications for the understanding of brain metabolic activity as well as the investigation of cerebrovascular disease. In this study, five normal volunteers were studied. All images were acquired on a Siemens 1.5 T scanner (Siemens Medical Systems Inc, Erlangen, Germany). Cerebral blood flow (CBF) was obtained in vivo with a dynamic imaging approach and the acquired images were post-processed with the singular value decomposition method (SVD). In addition, a multi-echo gradient echo/spin echo sequence was employed to provide MR estimates of oxygen extraction fraction (MR_OEF) in vivo. Subsequently, an absolute measure of MR cerebral metabolic rate of oxygen utilization (MR_CMRO2) was obtained in all subjects by taking the product of CBF and MR_OEF. A mean MR_CMRO2 of 28.94 ± 3.26 ml/min/100 g and 12.57 ± 3.11 ml/min/100 g was obtained for gray matter and white matter, respectively, suggesting that the gray matter utilizes more oxygen than white matter under normal physiological conditions. These results yield a gray matter to white matter CMRO2 ratio of 2.37 ± 0.37, which is comparable to the reported values in the literature. More studies are needed to further improve on the accuracy as well as shortening the required data acquisition time so that the proposed approaches can be utilized in a routine clinical setting. Copyright © 2001 John Wiley & Sons, Ltd.

Peripheral somatosensory fMRI in mouse at 11.7 T

Abstract: The feasibility of performing extremely-high resolution somatosensory fMRI in anesthetized mice using BOLD contrast at 11.7 T was investigated. A somatosensory stimulus was applied to the hindlimb of an α-chlorolose anesthetized mouse resulting in robust (p < 4 × 10−3) BOLD changes in somatosensory cortex and large veins. Percentage modulation of the MR signal in cortex exceeded 7%. Experiments that artificially modulated the inspired oxygen tension were also conducted; the results revealed large, heterogeneous, BOLD contrast changes in the mouse brain. In addition, T1, T2, and T2* values in gray matter at 11.7 T were evaluated. Discussion of the sensitivity limitations of BOLD fMRI in the tiny mouse central nervous system is presented. These methods show promise for the assessment of neurological function in mouse models of CNS injury and disease. Copyright © 2001 John Wiley & Sons, Ltd.

In vivo and in vitro NMR spectroscopy reveal a putative novel inborn error involving polyol metabolism.

Abstract: In vivo NMR spectroscopy was performed on the brain of a patient with a leukoencephalopathy, revealing unknown resonances between 3.5 and 4.0 ppm. In addition, urine and CSF of the patient were measured using high-resolution NMR spectroscopy. Also in these in vitro spectra, unknown resonances were observed in the 3.5-4.0 ppm region. Homonuclear (1)H two-dimensional J-resolved spectroscopy (JRES) and (1)H-(1)H correlation spectroscopy (COSY) were performed on the patient's urine for more accurate assignment of resonances. The NMR spectroscopic studies showed that the unknown resonances could be assigned to arabinitol and ribitol. This was confirmed using gas chromatography. The arabinitol was identified as D-arabinitol. The patient is likely to suffer from an as yet unknown inborn error of metabolism affecting D-arabinitol and ribitol metabolism. The primary molecular defect has not been found yet. Urine spectra of patients suffering from diabetes mellitus or galactosemia were recorded for comparison. Resonances outside the 3.2-4.0 ppm region, which are the most easy to recognize in body fluid spectra, allow easy recognition of various sugars and polyols. The paper shows that NMR spectroscopy in body fluids may help identifying unknown resonances observed in in vivo NMR spectra.

Assessment of brain tissue viability in acute ischemic stroke by BOLD MRI

Abstract: The introduction of new neuroprotective treatment strategies for acute stroke patients has provided a requirement for neuroimaging methods capable of identifying salvageable tissue in acute stroke patients. Substantial positron emission tomography evidence points to the fact that a peri-infarct zone with blood flow of 20–45% of normal, metabolic rate of oxygen of >35% of normal and oxygen extraction ratio (OER) of >0.7 are indices of tissue at risk of infarction, yet with potential for recovery. The sensitivity of T2 to blood oxygen level dependent (BOLD) effects allows the mismatch between oxygen delivery and consumption in the brain to be imaged. Previous evidence from animal models of cerebral hypoperfusion and ischemic stroke strongly suggest that T2 BOLD MRI highlights viable and salvageable brain regions. The Hahn-echo T2 and diffusion show distinct flow thresholds in the rat brain so that the former parameter probes areas with high OER and the latter genuine ischemia. In the flow-compromised tissue showing negative T2 BOLD, substantial residual perfusion is evident as revealed by bolus-tracking perfusion MRI, in agreement with the idea that tissue metabolic viability must be preserved for expression of BOLD. It is concluded that BOLD MRI may have potential for the assessment of tissue viability in acute ischemic stroke. Copyright © 2001 John Wiley & Sons, Ltd.

MR angiographic investigation of transient focal cerebral ischemia in rat.

Abstract: Contrast agent free time-of-flight magnetic resonance angiography (TOF-MRA) was applied to the intraluminal thread occlusion model of experimental stroke in rat. It was combined with perfusion- and diffusion-weighted imaging (PWI and DWI) sequences to correlate occlusion and reopening of the middle cerebral artery with alterations in these well-established magnetic resonance sequences. Since TOF-MRA can be repeated without limitations, the time course of vascular patency is demonstrated during an experimental period of up to 8 h (2 h control, 1 h ischemia, 3-6 h reperfusion). With an acquisition time of 10 min, TOF-MRA proved to be suitable to analyze the vascular state of occlusion and reperfusion repetitively in longitudinal studies. Spatial resolution was sufficient to observe neurovascular structural details. In eight out of 10 animals complete vessel occlusion by the intraluminal thread could be validated by an entirely extinguished signal of the ipsilateral middle cerebral artery (MCA) in the angiograms. This was in accordance with a perfusion deficit in the MCA vascular territory detected by PWI (reduction to 30.4 +/- 7.4% relative to contralateral side) and a disturbance of water ion homeostasis monitored by DWI in this area. One animal showed a delayed occlusion after 30 min of MCA occlusion, in another animal vessel occlusion failed. In seven out of the eight successful occlusion experiments there was immediate reperfusion after withdrawal of the thread. One animal showed a delayed reperfusion after suture retraction. Remarkable hemispheric differences in vascular branching of the MCA could be recognized in three out of 10 animals. In conclusion, TOF-MRA is considered a helpful method to survey even in small laboratory animals the correct time course of vascular occlusion and reopening in experimental ischemia, and provides complementary information to the tissue perfusion status monitored by PWI and the ischemic lesion territory detected by DWI.

Improved target volume characterization in stereotactic treatment planning of brain lesions by using high‐resolution BOLD MR‐venography

Abstract: In this methodological paper I report the stereotactic correlation of different magnetic resonance imaging (MRI) techniques [MR angiography (MRA), MRI, blood bolus tagging (STAR), functional MRI, and high-resolution BOLD venography (HRBV)] in patients with cerebral arterio-venous malformations (AVM) and brain tumors. The patient's head was fixed in a stereotactic localization system which is usable in both MR-systems and linear accelerator installations. Using phantom measurements global geometric MR image distortions can be 'corrected' (reducing displacements to the size of a pixel) by calculations based on modeling the distortion as a fourth-order two-dimensional polynomial. Further object-induced local distortions can be corrected by additionally measured field maps. Using this method multimodality matching could be performed automatically as long as all images are acquired in the same examination and the patient is sufficiently immobilized to allow precise definition of the target volume. Information about the hemodynamics of the AVM was provided by a dynamic MRA with the STAR technique, leading to an improved definition of the size of the nidus, the origin of the feeding arteries, whereas HRBV imaging yielded detailed and improved information about the venous pattern and drainage. In addition, functional MRI was performed in patients with lesions close to the primary motor cortex area, leading to an improved definition of structures at risk for the high-dose application in radiosurgery. In patients with brain tumors the potential of HRBV to probe tumor angiogenesis and its use in intensity-modulated treatment planning is still hampered by the open question of how to translate a BOLD signal pattern measured in the tumor to a dose distribution, which should be addressed in future studies.