Lithium spectroscopic imaging of rat brain at therapeutic doses

Since the discovery that lithium (Li) is efficacious for the treatment of manic depressive illness, the brain Li distribution of mammals treated with lithium has been of interest. However, the spatial relationship of lithium in the brain regions to its function remains largely unknown. Knowledge of Li distribution in the brain is necessary to localize its action in the brain. Both the therapeutic and neurotoxic side effects of Li are centered mainly in the central nervous system and hence there is considerable interest in understanding the extent of lithium penetration into the central nervous system. The mechanism by which neurotoxic side effects are generated is not known and may, in part, be related to the particular distribution of lithium in the brain. The regional specificity in lithium's brain distribution could underlie important steps on its action. Li levels in various brain regions for autopsied rats and humans have been reported. However, many results are conflicting due to ion redistribution at death or during sample preparation. A direct nondestructive measurement of Li levels in the brain where the drug exerts its effects is certainly desirable. Because magnetic resonance technique can be used to observe Li, it can be an appropriate method to monitor and map the distribution in the brain. The application of MR technology to rat brain regions has provided information on lithium distribution in a non-invasive manner. The earlier development work at lower field strengths provided brain lithium information at high dose of Li administration. Here we demonstrate the feasibility of quantitative spectroscopic imaging on rat brain under therapeutic doses.     

Fine-scale functional connectivity in somatosensory cortex revealed by high-resolution fMRI

High-resolution functional magnetic resonance imaging (fMRI) at high field (9.4 T) has been used to measure functional connectivity between subregions within the primary somatosensory (SI) cortex of the squirrel monkey brain. The hand-face region within the SI cortex of the squirrel monkey has been previously well mapped with functional imaging and electrophysiological and anatomical methods, and the orderly topographic map of the hand region is characterized by a lateral to medial representation of individual digits in four subregions of areas 3a, 3b, 1 and 2. With submillimeter resolution, we are able to detect not only the separate islands of activation corresponding to vibrotactile stimulations of single digits but also, in subsequent acquisitions, the degree of correlation between voxels within the SI cortex in the resting state. The results suggest that connectivity patterns are very similar to stimulus-driven distributions of activity and that connectivity varies on the scale of millimeters within the same primary region. Connectivity strength is not a reflection of global larger-scale changes in blood flow and is not directly dependent on distance between regions. Preliminary electrophysiological recordings agree well with the fMRI data. In human studies at 7 T, high-resolution fMRI may also be used to identify the same subregions and assess responses to sensory as well as painful stimuli, and to measure connectivity dynamically before and after such stimulations.     

STZ诱导大鼠1型糖尿病进行性脑萎缩的磁共振成像及组织化学研究

1型糖尿病(T1DM)是一种慢性代谢疾病,主要表现为胰岛素分泌量较正常情况下降,会对人体的多个器官和系统造成持续性的损伤．关于糖尿病的横向研究发现糖尿病患者相比于正常人存在着显著的脑萎缩,但关于糖尿病引起的脑萎缩随时间发生进行性改变的研究比较少见．实验采用腹腔注射链脲佐菌素(STZ)来诱导建立大鼠的1型糖尿病模型,运用磁共振成像(MRI)的方法对萎缩的脑区进行定位并在造模后12周和20周两个时间点对脑萎缩的程度进行对比分析,然后运用组织化学染色的方法观察在MRI上出现进行性萎缩的脑区中的神经元所发生的病理改变．MRI的结果表明：STZ诱导的T1DM大鼠相比于正常对照组大鼠出现了显著性的全脑体积、灰质体积和白质体积的萎缩,并且在多个白质脑区和灰质脑区均出现了萎缩程度随着病程的延长而逐渐加重．组织化学染色的结果发现,STZ诱导的T1DM大鼠相对于正常对照组大鼠在体感皮层、运动皮层和海马CA3区,均出现明显的神经元萎缩现象．     

10B-editing 1H-detection and 19F MRI strategies to optimize boron neutron capture therapy

Boron neutron capture therapy (BNCT) is a binary radiation therapy used to treat malignant brain tumours. It is based on the nuclear reaction (10B + n th --> [11B*] --> alpha + 7Li + 2.79 MeV) that occurs when 10B captures a thermal neutron to yield alpha particles and recoiling 7Li nuclei, both responsible of tumour cells destruction by short range and high ionization energy release. The clinical success of the therapy depends on the selective accumulation of the 10B carriers in the tumour and on the high thermal neutron capture cross-section of 10B. Magnetic resonance imaging (MRI) methods provide the possibility of monitoring, through 10B nuclei, the metabolic and physiological processes suitable to optimize the BNCT procedure. In this study, spatial distribution mapping of borocaptate (BSH) and 4-borono-phenylalanine (BPA), the two boron carriers used in clinical trials, has been obtained. The BSH map in excised rat brain and the 19F-BPA image in vivo rat brain, representative of BPA spatial distribution, were reported. The BSH image was obtained by means of double-resonance 10B-editing 1H-detection sequence, named M-Bend, exploiting the J-coupling interaction between 10B and 1H nuclei. Conversely, the BPA map was obtained by 19F-BPA using 19F-MRI. Both images were obtained at 7 T, in C6 glioma-bearing rat brain. Our results demonstrate the powerful of non conventional MRI techniques to optimize the BNCT procedure.     

NMR Studies of Intra- and Extracellular Red Blood Cell Lithium by Transverse Relaxation Measurements and Shift Reagents

Lithium salts are used in the treatment and prophylaxis of bipolar or mood disorders. The mechanism of action by which the cation exerts its therapeutic influence is unknown. A knowledge of brain Li concentration, its distribution in the brain, and its properties in the cellular microenvironment may have a strong influence on the understanding of Li function. The differentiation of lithium in the intra and extracellular environments has been achieved in a noninvasive manner in red blood cell (RBC) model. The two distinct transverse relaxation (T₂) components have been observed in the blood sample drawn from lithium treated rats. These results indicate two different environments for Li with a fast (T_2f) and a slow (T_2s) component in the RBC model corresponding fractions that contribute to each relaxation component. The results compare well with the intra- and extracellular RBC lithium measured using shift reagents. Our studies indicate that the T₂ method has utility in estimating the intracellular Li in systems that exhibit similar T₂ behavior. The studies performed at different Li doses in the rat model indicate that the method may have utility in following a wide range of intracellular Li.     

Spectroscopic imaging display and analysis.

A system for display of magnetic resonance (MR) spectroscopic imaging (SI) data is described which provides for efficient review and analysis of the multidimensional spectroscopic and spatial data format of this technique. Features include the rapid display of spectra from selected image voxels, formation of spectroscopic images, spectral and image data processing operations, methods for correlating spectroscopic image data with high resolution 1H MR images, and hardcopy facilities. Examples are shown for 31P and 1H spectroscopic imaging studies obtained in human and rat brain.     

About the limits of existence of α-cluster structure in nuclei

The shape of the d-α coincidence spectrum from the reaction ¹²C(⁶Li, d)¹⁶O(α)¹²C in the region corresponding to the 20.9 MeV 7^? level in ¹⁶O has been measured. Also, measurements of the α-particle elastic scattering excitation functions on ¹²C and ¹⁶O have been made in the regions corresponding to the α-cluster levels found in the (⁶Li, d) reactions. A comparison of the d-α coincidence spectra and excitation functions allows us to draw conclusions about splitting of the α-cluster states and region of their existence.     

Quantitative MRI of uterine leiomyomas during triptorelin treatment: Reproducibility of volume assessment and predictability of treatment response

Magnetic resonance (MR) imaging is increasingly applied for the quantitative evaluation of uterine leiomyomas. MR is thought to be more accurate in comparison to ultrasound (US) techniques. MR signal intensity (SI) may prove to be predictive of myoma response to GnRH agonist treatment. This study aimed to evaluate the precision of uterine volume assessment by a parallel planimetric MR method and the accuracy of the ellipsoid formula based calculations from MR and US images. It was also attempted to analyze the precision of MR leiomyoma volume measurements and examine the relation between pretreatment myoma SI patterns and the response to agonist therapy. Twenty-seven women with a myomatous uterus were scanned three times during GnRH agonist treatment for 6 months. T₁- and T₂-weighted, as well as T₁ contrast-enhanced sequences of the uterus were obtained in the transverse and sagittal plane. Abdominal US of the uterus was performed with a conventional sector scanner. By the use of a software system for analysis of three-dimensional images obtained by MR, uterine volume was measured by a parallel planimetric method (MR-ROI) as well as the use of the ellipsoid formula (MR-ELL). Myoma volume was assessed by the MR-ROI method. SI of the myomas was estimated from selected tissue samples as well as from the integral myoma region of interest. By abdominal US, volume was assessed by the ellipsoid equation (US-ELL). Within- and between-observer and method reliability (Rw/Rb) was calculated from mean squares obtained by analysis of variance. For uterine volume assessment, reliability between observers and between methods when the MR-ROI and MR-ELL methods were analyzed was excellent. For the US-ELL measurements, the between-observer reliability was limited. Moreover, the reliability of the US-ELL was low when the MR-ROI method was used as the standard. Myoma volume assessment with the MR-ROI method showed high between-observer and between-method agreement. The myoma/fat SI ratio and the mean SI coefficient of variation failed to show a correlation with the degree of response to triptorelin treatment of individual myomas. In MR uterine volume assessment the MR-ELL method is very accurate compared with the more complicated MR-ROI method. The agreement between MR and US is limited. Therefore, the ellipsoid method on MR images is to be regarded as the method of choice for quantitative assessment of uterine volume response to hormonal treatment. Myoma SI patterns were shown to be of no value in the response prediction of myomas to treatment with GnRH agonists.     

Dynamic multi-coil shimming of the human brain at 7 T

High quality magnetic field homogenization of the human brain (i.e. shimming) for MR imaging and spectroscopy is a demanding task. The susceptibility differences between air and tissue are a longstanding problem as they induce complex field distortions in the prefrontal cortex and the temporal lobes. To date, the theoretical gains of high field MR have only been realized partially in the human brain due to limited magnetic field homogeneity.A novel shimming technique for the human brain is presented that is based on the combination of non-orthogonal basis fields from 48 individual, circular coils. Custom-built amplifier electronics enabled the dynamic application of the multi-coil shim fields in a slice-specific fashion. Dynamic multi-coil (DMC) shimming is shown to eliminate most of the magnetic field inhomogeneity apparent in the human brain at 7 T and provided improved performance compared to state-of-the-art dynamic shim updating with zero through third order spherical harmonic functions. The novel technique paves the way for high field MR applications of the human brain for which excellent magnetic field homogeneity is a prerequisite.     

Phased array 3D MR spectroscopic imaging of the brain at 7 T

Ultra-high-field 7 T magnetic resonance (MR) scanners offer the potential for greatly improved MR spectroscopic imaging due to increased sensitivity and spectral resolution. Prior 7 T human single-voxel MR Spectroscopy (MRS) studies have shown significant increases in signal-to-noise ratio (SNR) and spectral resolution as compared to lower magnetic fields but have not demonstrated the increase in spatial resolution and multivoxel coverage possible with 7 T MR spectroscopic imaging. The goal of this study was to develop specialized radiofrequency (RF) pulses and sequences for three-dimensional (3D) MR spectroscopic imaging (MRSI) at 7 T to address the challenges of increased chemical shift misregistration, B1 power limitations, and increased spectral bandwidth. The new 7 T MRSI sequence was tested in volunteer studies and demonstrated the feasibility of obtaining high-SNR phased-array 3D MRSI from the human brain.     

Parametric multiecho proton spectroscopic imaging: Application to the rat brain in vivo

A parametric multiecho variant of proton spectroscopic imaging (SI) is presented using a multiecho SI sequence with uniform phase-encoding of all echoes within each echo train. The acquisition of SI data sets at different echo times (TE) increases the amount of information obtained within the same total measuring time as in standard SI measurements. The gain in information can be used: (a) to choose the most appropriate TE for each metabolite signal with respect to T₂, spin coupling, or problems caused by peak overlap; (b) to measure the relaxation time T₂ of metabolite signals with high spatial resolution; or (c) to improve the signal-to-noise ratio for metabolite signals with long T₂ values by adding spectra calculated from consecutive echoes. The method was tested in vivo on healthy rat brain and applied to study metabolic changes in rat brain lesions.     

In vivo MR evaluation of Gd-DTPA conjugated to dextran in normal rabbits.

A dextran-Gd-DTPA compound has been recently synthesized utilizing 70,800 Da molecular weight dextran. This polymeric contrast agent for magnetic resonance imaging has been found chemically to be very stable and to demonstrate in vitro improved relaxivities of 1.5 to 2.3 times that of monomeric Gd-DTPA at 100 MHz. This MR experiment examines the in vivo distribution and relaxivity of the 70,800 Da molecular weight dextran-Gd-DTPA compound in a rabbit model by measuring the change in signal-to-noise ratio of a variety of organs (renal cortex, renal medulla, liver, brain, and torcula herophile) compared to the preinjection state. Results demonstrate prolonged (beyond 60 min) enhancement of the renal cortex, renal medulla, liver and torcula, and no enhancement of brain parenchyma.     

Ovarian Brenner tumors: MR imaging characteristics

This study describes the appearance of Brenner tumors on MR imaging and compares quantitative signal intensity measurements of Brenner tumors with that of other ovarian tumors. A search of pathologic and MR records disclosed patients who had MRIs showing Brenner tumors prior to surgical excision. Patients (21) with other surgically proven ovarian masses were randomly selected for comparison. MR imaging was performed at 1.5 T with phased array multicoils and fast spin echo T2-weighted images. Region-of-interest measurements of signal intensity (SI) were made to calculate signal intensity ratios (SIR = mass SI/muscle SI). Brenner tumors showed significantly lower SIR than other tumors on T2-weighted images (p = 0 .004) and similar SIR on T1-weighted images. Brenner tumors show lower signal intensity on T2-weighted images than other non-fibrous ovarian tumors. This lower signal intensity may result from the extensive fibrous content of these tumors.     

MR image-based measurement of rates of change in volumes of brain structures. Part II: application to a study of Alzheimer's disease and normal aging

We present global and regional rates of brain atrophy measured on serially acquired T1-weighted brain MR images for a group of Alzheimer's disease (AD) patients and age-matched normal control (NC) subjects using the analysis procedure described in Part I. Three rates of brain atrophy: the rate of atrophy in the cerebrum, the rate of lateral ventricular enlargement and the rate of atrophy in the region of temporal lobes, were evaluated for 14 AD patients and 14 age-matched NC subjects. All three rates showed significant differences between the two groups. However, the greatest separation of the two groups was obtained when the regional rates were combined. This application has demonstrated that rates of brain atrophy, especially in specific regions of the brain, based on MR images can provide sensitive measures for evaluating the progression of AD. These measures will be useful for the evaluation of therapeutic effects of novel therapies for AD.     

Automatic segmentation for brain MR images via a convex optimized segmentation and bias field correction coupled model

Accurate segmentation of magnetic resonance (MR) images remains challenging mainly due to the intensity inhomogeneity, which is also commonly known as bias field. Recently active contour models with geometric information constraint have been applied, however, most of them deal with the bias field by using a necessary pre-processing step before segmentation of MR data. This paper presents a novel automatic variational method, which can segment brain MR images meanwhile correcting the bias field when segmenting images with high intensity inhomogeneities. We first define a function for clustering the image pixels in a smaller neighborhood. The cluster centers in this objective function have a multiplicative factor that estimates the bias within the neighborhood. In order to reduce the effect of the noise, the local intensity variations are described by the Gaussian distributions with different means and variances. Then, the objective functions are integrated over the entire domain. In order to obtain the global optimal and make the results independent of the initialization of the algorithm, we reconstructed the energy function to be convex and calculated it by using the Split Bregman theory. A salient advantage of our method is that its result is independent of initialization, which allows robust and fully automated application. Our method is able to estimate the bias of quite general profiles, even in 7T MR images. Moreover, our model can also distinguish regions with similar intensity distribution with different variances. The proposed method has been rigorously validated with images acquired on variety of imaging modalities with promising results.     

Comparison of MR perfusion imaging and microsphere measurements of regional cerebral blood flow in a rat model of middle cerebral artery occlusion

The purpose of this investigation was to correlate magnetic resonance (MR) perfusion measurements with absolute regional cerebral blood flow (rCBF) in a rat model of focal ischemia. The MR perfusion measurements were made using dynamic first-pass bolus tracking of a susceptibility contrast agent, whereas rCBF was measured using radioactive microspheres. Two simple MR perfusion parameters, the maximum change in ( ) and time delay to ( ), were derived from the signal intensity versus time curves on a pixel-to-pixel basis, without applying curve-fitting procedures or tracer kinetic theory. In each hemisphere, and were compared with the rCBF measurements in four selected regions of interest. Sixteen MR bolus tracking series were performed in 12 rats with occlusion of the middle cerebral artery. In all of the individual series there was a significant correlation (.0001 ≤ p ≤ .02) between and the microsphere rCBF measurements, with correlation coefficients ranging from .784 to .983. Pooling the data resulted in a correlation coefficient of .809 (p = .0001). There was a nonlinear correlation between the and rCBF. For both parameters there was considerable variation between different measurements regarding both the slope of the regression line and its intercept with the y-axis. Our results justify the use of as a relative measure of perfusion during acute cerebral ischemia. Because of the interindividual variation, calibration of MR perfusion measurements for the estimation of absolute flow values must be considered unreliable. The may have physiological relevance as a marker of collateral flow.     

Activation of Erk and JNK MAPK pathways by acute swim stress in rat brain regions

Background

The mitogen-activated protein kinases (MAPKs) have been shown to participate in a wide array of cellular functions. A role for some MAPKs (e.g., extracellular signal-regulated kinase, Erk1/2) has been documented in response to certain physiological stimuli, such as ischemia, visceral pain and electroconvulsive shock. We recently demonstrated that restraint stress activates the Erk MAPK pathway, but not c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) or p38MAPK, in several rat brain regions. In the present study, we investigated the effects of a different stressor, acute forced swim stress, on the phosphorylation (P) state of these MAPKs in the hippocampus, neocortex, prefrontal cortex, amygdala and striatum. In addition, effects on the phosphorylation state of the upstream activators of the MAPKs, their respective MAPK kinases (MAPKKs; P-MEK1/2, P-MKK4 and P-MKK3/6), were determined. Finally, because the Erk pathway can activate c-AMP response element (CRE) binding (CREB) protein, and swim stress has recently been reported to enhance CREB phosphorylation, changes in P-CREB were also examined.

Results

A single 15 min session of forced swimming increased P-Erk2 levels 2–3-fold in the neocortex, prefrontal cortex and striatum, but not in the hippocampus or amygdala. P-JNK levels (P-JNK1 and/or P-JNK2/3) were increased in all brain regions about 2–5-fold, whereas P-p38MAPK levels remained essentially unchanged. Surprisingly, levels of the phosphorylated MAPKKs, P-MEK1/2 and P-MKK4 (activators of the Erk and JNK pathways, respectively) were increased in all five brain regions, and much more dramatically (P-MEK1/2, 4.5 to > 100-fold; P-MKK4, 12 to ~300-fold). Consistent with the lack of forced swim on phosphorylation of p38MAPK, there appeared to be no change in levels of its activator, P-MKK3/6. P-CREB was increased in all but cortical (prefrontal, neocortex) areas.

Conclusions

Swim stress specifically and markedly enhanced the phosphorylation of the MAPKKs P-MEK1/2 and P-MKK4 in all brain regions tested without apparent alteration in the phosphorylation of P-MKK3/6. Curiously, phosphorylation of their cognate substrates (Erk and JNK) was increased to a much more modest extent, and in some brain regions was not altered. Similarly, there was a region-specific discrepancy between Erk and CREB phosphorylation. Possible explanations for these findings and comparison with the effects of restraint stress will be discussed.

     

The effect of sensorimotor activation on functional connectivity mapping with MRI

The correlations in the fluctuations in the blood oxygenation level-dependent (BOLD) MRI signal between anatomically distinct regions of the cortex that are known components of functional systems have been previously studied as possible indicators of functional connectivity. The objective of this study was to examine the effect of sensorimotor brain activity, as assessed by task-based functional magnetic resonance imaging (fMRI), on functional connectivity indices in the same region. Regions of activation for sequential finger motion were determined using a task-based, block-design fMRI study. Functional connectivity measurements based on interregional correlations were acquired at rest and during continuous, sequential finger motion. Connectivity indices were determined using normalized mean correlations within and between three regions of interest activated for the finger motion task. Connectivity indices were also determined for a control region that was not activated for the task. Continuous motor tasks performed during BOLD measurements did not significantly affect the functional connectivity as compared to the connectivity at rest within or between regions known to be activated by the task. However, there appeared to be a trend suggesting a slight reduction in connectivity indices during the motor task. The connectivity within and between those areas not activated for the task remained unchanged between conditions. These results suggest that in the motor system investigated, the recruitment of neurons to perform a specific task may moderately reduce the degree of hemodynamic coupling within and between regions.     

Mapping phosphorylation rate of fluoro-deoxy-glucose in rat brain by F chemical shift imaging

¹⁹F magnetic resonance spectroscopy (MRS) studies of 2-fluoro-2-deoxy-d-glucose (FDG) and 2-fluoro-2-deoxy-d-glucose-6-phosphate (FDG-6P) can be used for directly assessing total glucose metabolism in vivo. To date, ¹⁹F MRS measurements of FDG phosphorylation in the brain have either been achieved ex vivo from extracted tissue or in vivo by unusually long acquisition times. Electrophysiological and functional magnetic resonance imaging (fMRI) measurements indicate that FDG doses up to 500 mg/kg can be tolerated with minimal side effects on cerebral physiology and evoked fMRI-BOLD responses to forepaw stimulation. In halothane-anesthetized rats, we report localized in vivo detection and separation of FDG and FDG-6P MRS signals with ¹⁹F 2D chemical shift imaging (CSI) at 11.7 T. A metabolic model based on reversible transport between plasma and brain tissue, which included a non-saturable plasma to tissue component, was used to calculate spatial distribution of FDG and FDG-6P concentrations in rat brain. In addition, spatial distribution of rate constants and metabolic fluxes of FDG to FDG-6P conversion were estimated. Mapping the rate of FDG to FDG-6P conversion by ¹⁹F CSI provides an MR methodology that could impact other in vivo applications such as characterization of tumor pathophysiology.     

30MeV/u 40Ar+112,124Sn反应中的同位素产额比与核温度

系统研究了30MeV/u^40Ar ^112,124Sn反应中的轻粒子同位素产额比随角度和初始激发能的变化关系,对于两个反应体系,均观察到3He/^4He和^6Ni/^7Li的产额比随角度的增加而增加,^6He/^4He和^8Li/^7Li随角度的增加而减少,统计发射的运动学效应不能完全符合实验结果,各种单同位素产额比与靶核的N／Z比有关,表现出同位旋效应,而由双同位素比提取的核温度几乎没有靶核相关性。