Automatic segmentation of brain white matter and white matter lesions in normal aging: comparison of five multispectral techniques

White matter loss, ventricular enlargement and white matter lesions are common findings on brain scans of older subjects. Accurate assessment of these different features is therefore essential for normal aging research. Recently, we developed a novel unsupervised classification method, named ‘Multispectral Coloring Modulation and Variance Identification’ (MCMxxxVI), that fuses two different structural magnetic resonance imaging (MRI) sequences in red/green color space and uses Minimum Variance Quantization (MVQ) as the clustering technique to segment different tissue types. Here we investigate how this method performs compared with several commonly used supervised image classifiers in segmenting normal-appearing white matter, white matter lesions and cerebrospinal fluid in the brains of 20 older subjects with a wide range of white matter lesion load and brain atrophy. The three tissue classes were segmented from T₁-, T₂-, T₂?- and fluid attenuation inversion recovery (FLAIR)-weighted structural MRI data using MCMxxxVI and the four supervised multispectral classifiers available in the Analyze package, namely, Back-Propagated Neural Networks, Gaussian classifier, Nearest Neighbor and Parzen Windows. Bland–Altman analysis and Jaccard index values indicated that, in general, MCMxxxVI performed better than the supervised multispectral classifiers in identifying the three tissue classes, although final manual editing was still required to deliver radiologically acceptable results. These analyses show that MVQ, as implemented in MCMxxxVI, has the potential to provide quick and accurate white matter segmentations in the aging brain, although further methodological developments are still required to automate fully this technique.     

Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen,a new dopaminergic agent

The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate.The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) − a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-mediated metabolism of drug-like molecules.Wistar rats, subjected to two different behavioural studies in which DA-Phen was intraperitoneally administrated at a dose equal to 0.03 mmol/kg, were sacrificed after the experimental protocols and their major organs were analysed to quantify the drug uptake. The data obtained were integrated with in silico prediction of potential metabolites of DA-Phen using the SmartCYP predictive tool.DA-Phen reached quantitatively the Central Nervous System and the results showed that the amide bond of the DA-Phen is scarcely hydrolysed as it was found intact in analyzed organs. As a consequence, it is possible to assume that DA-Phen acts as dopaminergic modulator per se and not as a Dopamine prodrug, thus avoiding peripheral release and toxic side effects due to the endogenous neurotransmitter.Furthermore the identification of potential metabolites related to biotransformation of the drug candidate leads to a more careful evaluation of the appropriate route of administration for future intended therapeutic aims and potential translation into clinical studies.     

脑功能核磁共振成像在精神疾病中的应用

主要介绍了几种脑功能核磁共振成像方法以及在精神疾病中的研究情况.血氧水平依赖fMRI (BOLD-fMRI)是目前应用最广泛的fMRI技术,可利用神经激活后对局部血流的影响,间接显示神经活动.灌注加权成像是直接测定脑血流的fMRI技术,但由于它的时间分辨率比较低,对快速的脑功能难以进行研究.扩散加权象目前主要用于脑缺血的早期诊断,利用该技术也可示踪神经通路.化学位移成像能够检测局部组织代谢产物的含量,可反映不同脑区能量和物质代谢的状况,也是一种脑功能的研究手段.尽管这些技术在神经、心理学领域已经取得非常可喜的进展,目前fMRI在精神疾病方面的工作较少,相信随着技术的改进,fMRI必将在精神疾病方面大显身手.     

Spectral localization of arbitrarily shaped regions of interest (SLASH) using single voxel signals

A method for obtaining localized spectra from arbitrarily shaped regions of interest is described. When a sample consists of homogeneous compartments or domains, spectra localized in each compartment can be obtained from signals of single voxels with regular shapes by solving a set of simultaneous linear equations. Experimental demonstrations on a phantom and on human brain in vivo for a two compartment, two voxel case are presented. The issue of signal-to-noise ratio is also discussed.     

Tripodal amphiphilic pseudopeptidic nanovesicles as p-coumaric acid delivery systems for brain cancer cells

Nanovesicles based on tripodal amphiphilic pseudopeptides are prepared as carriers for p-coumaric acid (p-CA) delivery. Loaded nanovesicles are obtained by both thin film hydration and ethanol injection methods with positive Z-potential values. The last technique renders lower particle sizes and excellent polydispersity index, with average values of 130 nm and 0.123, respectively, although the drug loading obtained after ultracentrifugation is lower. In vitro release experiments, including the use of different external stimuli such as pH and proteolytic enzymes, provide interesting results. The prepared nanovesicles are tested on normal cells (VERO), displaying a high safety profile scoring with a 50% inhibitory concentration (IC₅₀) of 1,822 μg/mL. A 40-times increase in the in vitro cytotoxic effect of p-CA on Glioma GL261 brain cancer cells, from IC₅₀ 1,082 μg/mL to 29 μg/mL, is observed using the loaded pseudopeptide nanovesicles. ¹H NMR studies reveal that the drug is mainly located inside the nanoparticle bilayer. Transmembrane carboxyfluorescein studies reveal that the amphiphilic compound does not provide a significant membrane fluidification. Experimental data suggest that the observed biological activity can be associated to an enhanced permeability and retention effect. The present results highlight the potential of such nanovesicles as potent p-CA carriers for brain cancer therapy.     

Effects of cocaine on blood flow and oxygen metabolism in the rat brain: implications for phMRI

The effects of cocaine on cerebral blood flow and tissue oxygen levels in the rat brain were investigated with concurrent laser Doppler flowmetry and fluorescence quenching spectroscopy. Responses elicited by mild hypercapnia were used as calibration to assess the effects of cocaine on oxidative metabolism. Intravenous cocaine challenge of 0.5 mg/kg induced significant increases in tissular oxygenation and perfusion in all regions investigated (primary motor cortex, medial prefrontal cortex and dorsal striatum). Mild hypercapnia, a challenge that affects haemodynamics but not metabolism, elicited comparable changes in blood flow but substantially larger changes in tissue oxygen levels. These differences in tissue oxygen build-up suggest that increased oxidative metabolism is a significant component of the cerebral metabolic response to acute cocaine challenge. The implications for the interpretation of pharmacological MRI data are discussed.     

A novel functional magnetic resonance imaging compatible search-coil eye-tracking system

Measuring eye movements (EMs) using the search-coil eye-tracking technique is superior to video-based infrared methods [Collewijn H, van der Mark F, Jansen TC. Precise recording of human eye movements. Vision Res 1975;15(3):447-50], which suffer from the instability of pupil size, blinking behavior and lower temporal resolution. However, no conventional functional magnetic resonance imaging (fMRI)-compatible search-coil eye tracker exists. The main problems for such a technique are the interaction between the transmitter coils and the magnetic gradients used for imaging as well as the limited amount of space in a scanner. Here we present an approach to overcome these problems and we demonstrate a method to record EMs in an MRI scanner using a search coil. The system described has a spatial resolution of 0.07 degrees (visual angle) and a high temporal resolution (22 kHz). The transmitter coils are integrated into the visual presentation system and the control/analysis unit is portable, which enables us to integrate the eye tracker with an MRI scanner. Our tests demonstrate low noise in the recorded eye traces and scanning with minimal artifact. Furthermore, the induced current in the search coil caused by the RF pulses does not lead to measurable heating. Altogether, this MR-compatible search-coil eye tracker can be used to precisely monitor EMs with high spatial and temporal resolution during fMRI. It can therefore be of great importance for studies requiring accurate fixation of a target, or measurement and study of the subject's oculomotor system.     

Multilevel Functional Principal Component Analysis for High-Dimensional Data

We propose fast and scalable statistical methods for the analysis of hundreds or thousands of high-dimensional vectors observed at multiple visits. The proposed inferential methods do not require loading the entire dataset at once in the computer memory and instead use only sequential access to data. This allows deployment of our methodology on low-resource computers where computations can be done in minutes on extremely large datasets. Our methods are motivated by and applied to a study where hundreds of subjects were scanned using Magnetic Resonance Imaging (MRI) at two visits roughly five years apart. The original data possess over ten billion measurements. The approach can be applied to any type of study where data can be unfolded into a long vector including densely observed functions and images. Supplemental materials are provided with source code for simulations, some technical details and proofs, and additional imaging results of the brain study.     

Magnetic resonance elastography of the brain in a mouse model of Alzheimer's disease: initial results

The increasing prevalence of Alzheimer's disease (AD) has provided motivation for developing novel methods for assessing the disease and the effects of potential treatments. Magnetic resonance elastography (MRE) is an MRI-based method for quantitatively imaging the shear tissue stiffness in vivo. The objective of this research was to determine whether this new imaging biomarker has potential for characterizing neurodegenerative disease. Methods were developed and tested for applying MRE to evaluate the mouse brain, using a conventional large bore 3.0T MRI system. The technique was then applied to study APP-PS1 mice, a well-characterized model of AD. Five APP-PS1 mice and 8 age-matched wild-type mice were imaged immediately following sacrifice. Brain shear stiffness measurements in APP-PS1 mice averaged 22.5% lower than those for wild-type mice (P = .0031). The results indicate that mouse brain MRE is feasible at 3.0T, and brain shear stiffness has merit for further investigation as a potential new biomarker for Alzheimer's disease.