Manganese-enhanced magnetic resonance imaging (MEMRI)

Manganese ion (Mn2+) is an essential metal that participates as a cofactor in a number of critical biological functions, such as electron transport, detoxification of free radicals and synthesis of neurotransmitters. Mn2+ can enter excitable cells using some of the same transport systems as Ca2+ and it can bind to a number of intracellular sites because it has high affinity for Ca2+ and Mg2+ binding sites on proteins and nucleic acids. Paramagnetic forms of manganese ions are potent MRI relaxation agents. Indeed, Mn2+ was the first contrast agent proposed for use in MRI. Recently, there has been renewed interest in combining the strong MRI relaxation effects of Mn2+ with its unique biology, in order to further expand the already broad assortment of useful information that can be measured by MRI. Such an approach has been continuously developed in the past several years to provide unique tissue contrast, to assess tissue viability, to act as a surrogate marker of calcium influx into cells and to trace neuronal connections. This special issue of NMR in Biomedicine on manganese-enhanced MRI (MEMRI) is aimed at providing the readers of this journal with an extensive review of some of the most prominent applications of MEMRI in biological systems. Written by several of the leaders in the field, the reviews and original research articles featured in this special issue are likely to offer an exciting and inspiring view of the broad range of applications of MEMRI.     

Manganese-enhanced magnetic resonance imaging (MEMRI) of mouse brain development

Given the importance of genetically modified mice in studies of mammalian brain development and human congenital brain diseases, MRI has the potential to provide an efficient in vivo approach for analyzing mutant phenotypes in the early postnatal mouse brain. The combination of reduced tissue contrast at the high magnetic fields required for mice, and the changing cellular composition of the developing mouse brain make it difficult to optimize MRI contrast in neonatal mouse imaging. We have explored an easily implemented approach for contrast-enhanced imaging, using systemically administered manganese (Mn) to reveal fine anatomical detail in T1-weighted MR images of neonatal mouse brains. In particular, we demonstrate the utility of this Mn-enhanced MRI (MEMRI) method for analyzing early postnatal patterning of the mouse cerebellum. Through comparisons with matched histological sections, we further show that MEMRI enhancement correlates qualitatively with granule cell density in the developing cerebellum, suggesting that the cerebellar enhancement is due to uptake of Mn in the granule neurons. Finally, variable cerebellar defects in mice with a conditional mutation in the Gbx2 gene were analyzed with MEMRI to demonstrate the utility of this method for mutant mouse phenotyping. Taken together, our results indicate that MEMRI provides an efficient and powerful in vivo method for analyzing neonatal brain development in normal and genetically engineered mice.     

Manganese-enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations

Manganese-enhanced MRI (MEMRI) is being increasingly used for MRI in animals due to the unique T1 contrast that is sensitive to a number of biological processes. Three specific uses of MEMRI have been demonstrated: to visualize activity in the brain and the heart; to trace neuronal specific connections in the brain; and to enhance the brain cytoarchitecture after a systemic dose. Based on an ever-growing number of applications, MEMRI is proving useful as a new molecular imaging method to visualize functional neural circuits and anatomy as well as function in the brain in vivo. Paramount to the successful application of MEMRI is the ability to deliver Mn2+ to the site of interest at an appropriate dose and in a time-efficient manner. A major drawback to the use of Mn2+ as a contrast agent is its cellular toxicity. Therefore, it is critical to use as low a dose as possible. In the present work the different approaches to MEMRI are reviewed from a practical standpoint. Emphasis is given to the experimental methodology of how to achieve significant, yet safe, amounts of Mn2+ to the target areas of interest.     

Manganese-enhanced magnetic resonance imaging (MEMRI) without compromise of the blood-brain barrier detects hypothalamic neuronal activity in vivo

There is growing interest in the use of manganese-enhanced MRI (MEMRI) to detect neuronal activity and architecture in animal models. The MEMRI neuronal activity studies have been generally performed either by stereotactic brain injection or by systemic administration of Mn(2+) in conjunction with the disruption of the blood-brain barrier (BBB). These approaches, however, have limited the use of MEMRI because of the procedure-related morbidity/mortality or because brain activity measured by these methods can diverge from genuine physiological responses. In this study, the hypothesis that MEMRI, performed with systemic administration of Mn(2+) without compromising the BBB integrity, is able to detect hypothalamic function associated with feeding was tested. This procedure was tested on a simple physiological condition, fasting, and with this method temporal and regional differences in Mn(2+) enhancement could be detected. It is concluded that MEMRI can be used to study hypothalamic function in the murine brain without compromising the BBB. It was also shown that region-specific Mn(2+) enhancement in the mouse brain can be modulated by fasting. More importantly, this non-invasive in vivo imaging technique is able to demonstrate differences in brain activities, previously possible only by in vitro studies.     

Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to image brain plasticity in song birds

The song control system of song birds is an excellent model for studying brain plasticity and has thus far been extensively analyzed by histological and electrophysiological methods. However, these approaches do not provide a global view of the brain and/or do not allow repeated measures, which are necessary to establish correlations between alterations in neural substrate and behavior. Application of in vivo manganese-enhanced MRI enabled us for the first time to visualize the song control system repeatedly in the same bird, making it possible to quantify dynamically the volume changes in this circuit as a function of seasonal and hormonal influences. In this review, we introduce and explore the song control system of song birds as a natural model for brain plasticity to validate a new cutting edge technique, which we called 'repeated dynamic manganese enhanced MRI' or D-MEMRI. This technique is based on the use of implanted permanent cannulae--for accurate repeated manganese injections in a defined target area--and the subsequent MRI acquisition of the dynamics of the accumulation of manganese in projection brain targets. A compilation of the D-MEMRI data obtained thus far in this system demonstrates the usefulness of this new method for studying brain plasticity. In particular it is shown to be a perfect tool for long-term studies of morphological and functional responses of specific brain circuits to changes in endocrine conditions. The method was also successfully applied to obtain quantitative measures of changes in activity as a function of auditory stimuli in different neuronal populations of a same nucleus that project to different targets. D-MEMRI, combined with other MRI techniques, clearly harbors potential for unraveling seasonal, hormonal, pharmacological or even genetically driven changes in a neuronal circuit, by simultaneously measuring changes in morphology, activity and connectivity.     

Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to imaging of the heart

The use of manganese-based MRI contrast materials, either manganese salts or chelates, has spanned the entire timeframe of cardiac MRI. However interest in Mn compounds for cardiac MRI has been sporadic because of concerns over cardiotoxicity associated with significant concentration of free Mn2+ and notable success of gadolinium chelates in cardiac application. Initial strategies to overcome cardiotoxicity included chelation of Mn2+ to reduce the concentration of the free ion in vivo, and addition of Ca2+ in combination with Mn2+ to competitively reduce binding of Mn2+ to Ca2+ channels in the heart. Both approaches met with mixed success, but were subsequently discontinued in favor of gadolinium-based approaches. However Mn2+-based media potentially offer unique advantages for characterizing heart pathology over conventional Gd-based contrast media because Mn2+ is taken up by heart cells and retained for hours. Cellular uptake occurs through calcium channels so contrast on delayed images may be interpreted according to regional or global functional status. Since Mn2+ is retained in the heart, Mn-based media can be administered outside the magnet and the contrast pattern measured hours later to provide assessment of uptake. A key issue is whether sufficient accumulation of Mn2+ in heart cells for imaging can occur without cardiotoxicity, and findings to date indicate this is possible. This review examines the current status of Mn2+-enhanced MRI of heart with particular focus on the hypothesis that Mn2+ uptake can be interpreted in terms of heart function.     

In vivo, trans-synaptic tract-tracing utilizing manganese-enhanced magnetic resonance imaging (MEMRI)

It is well established that manganese ion (Mn2+) can access neurons through voltage-gated calcium (Ca2+) channels. Based upon this fundamental principle, Mn2+ has long been used in biomedical research as an indicator of Ca2+ influx in conjunction with fluorescent microscopy. Additionally, after entry into neurons, Mn2+ is transported down axons via microtubule based fast axonal transport. Furthermore, Mn2+ is paramagnetic, resulting in a shortening of the spin-lattice relaxation time-constant, T1, which yields positive contrast enhancement in T1-weighted MRI images, specific to tissues where the ion has accumulated. Manganese-enhanced MRI (MEMRI) utilizes a combination of these properties of Mn2+ to trace neuronal pathways in an MRI-detectable manner. The focus of this review will detail some of the current MEMRI tract-tracing methodologies in mice and non-human primates as well as biological applications of MEMRI tract-tracing.     

Trifluoromethoxy-benzylated ligands improve amyloid detection in the brain using (19)F magnetic resonance imaging

The chemical properties of probes that improve amyloid detection by non-invasive (19)F magnetic resonance imaging (MRI) are of interest. We synthesized benzoxazole compounds with trifluoromethoxy groups, and found that these compounds displayed sharp (19)F nuclear magnetic resonance (NMR) signals in an assay buffer. However, the intensities of the (19)F NMR signals were dramatically reduced in mouse brain lysates. Our results indicate that the inhibitory effect of brain tissue on the (19)F NMR signals from these probes can be attributed to the hydrophobicity of the tissue. These results highlight the importance of using hydrophilic (19)F-MRI agents to avoid the inhibitory effects of brain tissues on (19)F NMR signals.     

咀嚼时局部脑活动的功能性核磁共振成像

目的：应用功能性核磁共振成像（fMRI）探测人吸嚼时的大脑功能活动。方法：要求人在无任何其它躯体活动条件下咀嚼肌以10s运动20s休息的频率进行。选用8例成人冠状切面和横轴面的头部磁共振片,观察脑功能活动情况。结果：①在咀嚼时脑的广泛区域是激活的;②在相对应的咀嚼活动中有优势半球的激活区;③第I躯体感觉区激活的方式远较第I躯体运动区多样化;④在额叶中4例年轻观察对象出现了广泛的神经元激活区,但在老年人很少出现这样的激活区。结论：咀嚼活动除了它本身的功能运动外,在维持脑的活动方面具有重要的作用。同时也说明fMRI在研究活体人脑功能活动方面是一个相当有效的方法。     

Wavelet compression on detection of brain lesions with magnetic resonance imaging

The purpose of this report is to assess clinically acceptable compression ratios on the detection of brain lesions at magnetic resonance imaging (MRI). Four consecutive T2-weighted and the corresponding T1-weighted images obtained in 20 patients were studied for 109 anatomic sites including 50 with lesions and 59 without lesions. The images were obtained on a 1.5-T MR unit with a pixel size of 0.9 to 1.2 x 0.47 mm and a section thickness of 5 mm. The image data were compressed by wavelet-based algorithm at ratios of 20:1, 40:1, and 60:1. Three radiologists reviewed these images on an interactive workstation and rated the presence or absence of a lesion with a 50 point scale for each anatomic site. The authors also evaluated the influence of pixel size on the quality of image compression. At receiver operating characteristic (ROC) analysis, no statistically significant difference was detected at a compression ratio of 20:1. A significant difference was observed with 40:1 compressed images for one reader (P = .023), and with 60:1 for all readers (P = .001 to .012). A root mean squared error (RMSE) was higher in 0.94- x 0.94-mm pixel size images than in 0.94- x 0.47-mm pixel size images at any compression ratio, indicating compression tolerance is lower for the larger pixel size images. The RMSE, subjective image quality, and error images of 10:1 compressed 0.94- x 0.94-mm pixel size images were comparable with those of 20:1 compressed 0.94- x 0.47-mm pixel size images. Wavelet compression can be acceptable clinically at ratios as high as 20:1 for brain MR images when a pixel size at image acquisition is around 1.0 x 0.5 mm, and as high as 10:1 for those with a pixel size around 1.0 x 1.0 mm.     

大脑功能磁共振成像基础研究进展

大脑功能区的定位一直是基础研究学者研究的热点，近年来功能磁共振成像(fMRI)作为一种新型无损伤技术，为大脑功能的基础研究提供了一个新的途径。fMRI以其高分辨成像技术适时反应脑神经活动时的功能变化，藉以了解在生命状态下大脑不同区域的主要功能和疾病时的功能改变。这是目前人们所掌握的唯一无侵入、无创伤、可精确定位人脑高级功能的研究手段：广义上fMRI方法包括脑血流测定技术、脑代谢测定技术、     

Pulse sequence generated oblique magnetic resonance imaging: applications to cardiac imaging

A pulse sequence procedure for producing oblique magnetic resonance images is described. Using this procedure we present a new, accurate method to obtain true short-axis views and true long-axis views (both parallel and perpendicular to the septal plane) of the heart. The method is accurate regardless of the orientation of patient's heart. The method does not require the patient to be rotated, nor otherwise moved, and does not require any additional hardware. The method is experimentally verified with both human and phantom studies. The phantom study indicates accuracy of approximately 1 degree with a commercial scanner that reports angular measurements to a precision of 1 degree. Application of the short-axis views to measurement of left ventricular volume, and possible advantages of Gauss-Legendre integration for this measurement are discussed. Finally, multiphase oblique cardiac images are presented.     

Forebrain ischemia studied using magnetic resonance imaging and spectroscopy

A combination of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) has been used to follow the time course of changes resulting from forebrain ischemia in the rat. The 31P MRS demonstrates that the level of high energy metabolites decreases significantly during the 10 min ischemic period but returns to normal after 1 h of reperfusion. MRI shows no change after 1 h of reperfusion but significant changes in the striatum after 24 h and in the hippocampus after 48 h. These changes correlate well with histopathology. Diabetic rats have shown the effect of hyperglycemia in accentuation of ischemic and post ischemic pH changes. Conversely, diabetic rats maintained severely hypoglycemic with insulin showed little variation in pH during or following the ischemic insult. The results emphasize the importance of both MRS and MRI in following the temporal profile and distribution of ischemic neuronal injury.     

Diffusion magnetic resonance imaging: Its principle and applications

Diffusion magnetic resonance imaging (MRI) is one of the most rapidly evolving techniques in the MRI field. This method exploits the random diffusional motion of water molecules, which has intriguing properties depending on the physiological and anatomical environment of the organisms studied. We explain the principles of this emerging technique and subsequently introduce some of its present applications to neuroimaging, namely detection of ischemic stroke and reconstruction of axonal bundles and myelin fibers. Anat Rec (New Anat) 257:102–109, 1999. © 1999 Wiley‐Liss, Inc.     

Diffusion magnetic resonance imaging: its principle and applications.

Diffusion magnetic resonance imaging (MRI) is one of the most rapidly evolving techniques in the MRI field. This method exploits the random diffusional motion of water molecules, which has intriguing properties depending on the physiological and anatomical environment of the organisms studied. We explain the principles of this emerging technique and subsequently introduce some of its present applications to neuroimaging, namely detection of ischemic stroke and reconstruction of axonal bundles and myelin fibers.     

Use of postmortem brain magnetic resonance imaging at autopsy

The study was undertaken to define the possibilities of using postmortem MRI for examining the brain. A complex study was made to explore 21 neutral formalin-fixed gross brain specimens from patients with neurosurgical pathology. Macroscopic and target histological studies of the changed signal areas detected by MRI were performed using histochemical stains. The significance of the results obtained by MRI in vitro has been defined, which furnish considerable opportunities to use the technique for the postmortem diagnosis of various diseases, to detect macroscopically undetectable changes (perifocal changes, metastases), to make a complex of intractable diagnostic problems, and to study the histological substrate of changed MR signal areas.     

Simultaneous assessment of left-ventricular infarction size, function and tissue viability in a murine model of myocardial infarction by cardiac manganese-enhanced magnetic resonance imaging (MEMRI)

Owing to its signal-enhancing characteristics in viable well-perfused tissue, divalent manganese (Mn2+) has been used as a myocardial imaging contrast agent. Because Mn2+ can enter excitable cells through the voltage-gated L-type calcium channels, manganese-enhanced MRI (MEMRI) has been used to determine the viability and the inotropic state of the heart. In this study, we examined the correlation between left ventricular infarction zone as assessed by cardiac MEMRI and function in mice with permanent coronary artery occlusion. At an Mn2+ infusion dose of 1.72+/-0.47 nmol/min/g body weight, the steady-state signal intensity (SI) enhancement 20-26 min post-Mn2+ infusion of the normal septum and left-ventricular wall during diastole was 128.2+/-14.4 and 127.9+/-26.5%, respectively, whereas the infarction zone was 56.0+/-7.1%. During systole, the SI enhancement was 144.6+/-33.0, 116.0+/-18.7 and 48.3+/-20.0% for the normal septum, left-ventricular wall and infarction zone, respectively. A good correlation was obtained between the MEMRI determined infarction volume and conventional histological TTC staining (r = 0.9582, p<0.01). There was also a strong negative correlation between MEMRI determined infarction percentage (compared with whole left ventricle) and ejection fraction (r = -0.94, p<0.05). These data suggest that the Mn2+ concentration at steady state in the heart may reflect altered tissue viability in the infarcted tissue as well as surrounding region following myocardial infarction. In conclusion, in vivo cardiac MEMRI offers a manner in which functional, pathologic and viability data may be obtained simultaneously in myocardial tissue.     

Enhancing magnetic resonance imaging tumor detection with fluorescence intensity and lifetime imaging

Early detection is important for many solid cancers but the images provided by ultrasound, magnetic resonance imaging (MRI), and computed tomography applied alone or together, are often not sufficient for decisive early screening ∕ diagnosis. We demonstrate that MRI augmented with fluorescence intensity (FI) substantially improves detection. Early stage murine pancreatic tumors that could not be identified by blinded, skilled observers using MRI alone, were easily identified with MRI along with FI images acquired with photomultiplier tube detection and offset laser scanning. Moreover, we show that fluorescence lifetime (FLT) imaging enables positive identification of the labeling fluorophore and discriminates it from surrounding tissue autofluorescence. Our data suggest combined-modality imaging with MRI, FI, and FLT can be used to screen and diagnose early tumors.     

磁共振谱成像(MRSI)技术的研究进展

磁共振谱成像 (MRSI)在临床诊断中的作用越来越大。目前 ,最有效的快速谱成像法有回波平面法、螺旋轨迹法和阵列采集法。但是 ,这些 MRSI方法的数据采集时间仍然很长 ,速度有待于进一步提高。抑水抑脂脉冲序列基本定型 ,改进的余地不大。在定量的谱分析方面 ,已经实现分析自动化。谱参数估计方法基本完善 ,但在强基线信号时参数估计方法有待于深入研究。目前 ,磁共振谱的图像重建方法局限在 FFT或网格化后的 FFT,这些方法比较简单、快速 ,但也局限了采样脉冲序列 (采样轨迹 )的大胆设计。期望研究出速度更快的 MRSI数据采集脉冲序列。     

Ischaemic preconditioning in the rat brain: a longitudinal magnetic resonance imaging (MRI) study

Ischaemic preconditioning in rats was studied using MRI. Ischaemic preconditioning was induced, using an intraluminal filament method, by 30 min middle cerebral artery occlusion (MCAO), and imaged 24 h later. The secondary insult of 100 min MCAO was induced 3 days following preconditioning and imaged 24 and 72 h later. Twenty-four hours following ischaemic preconditioning most rats showed small sub-cortical hyperintense regions not seen in sham-preconditioned rats. Twenty-four hours and 72 h following the secondary insult preconditioned animals showed significantly smaller lesions (24 h = 112 +/- 31 mm(3), mean +/- standard error; 72 h = 80 +/- 35 mm(3)), which were confined to the striatum, than controls (24 h = 234 +/- 32 mm(3), p = 0.026; 72 h = 275 +/- 37 mm(3), p = 0.003). In addition during lesion maturation from 24 to 72 h post-secondary MCAO, preconditioned rats displayed an average reduction in lesion size as measured by MRI whereas sham-preconditioned rats displayed increases in lesion size; this is the first report of such differential lesion volume evolution in cerebral ischaemic preconditioning. Copyright -Copyright 2001 John Wiley & Sons, Ltd.