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Visualization of live, mammalian neurons during Kainate-infusion using magnetic resonance microscopy.

ABSTRACT: Since its first description and development in the late 20th century, diffusion magnetic resonance imaging (dMRI) has proven useful in describing the microstructural details of biological tissues. Signal generated from the protons of water molecules undergoing Brownian motion produces contrast based on the varied diffusivity of tissue types. Images employing diffusion contrast were first used to describe the diffusion characteristics of tissues, later used to describe the fiber orientations of white matter through tractography, and most recently proposed as a functional contrast method capable of delineating neuronal firing in the active brain. Thanks to the molecular origins of its signal source, diffusion contrast is inherently useful at describing features of the microenvironment; however, limitations in achievable resolution in magnetic resonance imaging (MRI) scans precluded direct visualization of tissue microstructure for decades following MRI's inception as an imaging modality. Even after advancements in MRI hardware had permitted the visualization of mammalian cells, these specialized systems could only accommodate fixed specimens that prohibited the observation and characterization of physiological processes. The goal of the current study was to visualize cellular structure and investigate the subcellular origins of the functional diffusion contrast mechanism (DfMRI) in living, mammalian tissue explants. Using a combination of ultra-high field spectrometers, micro radio frequency (RF) coils, and an MRI-compatible superfusion device, we are able to report the first live, mammalian cells-?-motor neurons-visualized with magnetic resonance microscopy (MRM). We are also able to report changes in the apparent diffusion of the stratum oriens within the hippocampus-a layer comprised primarily of pyramidal cell axons and basal dendrites-and the spinal cord's ventral horn following exposure to kainate.

SUBMITTER: Flint JJ

PROVIDER: S-EPMC7510773 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Visualization of live, mammalian neurons during Kainate-infusion using magnetic resonance microscopy.

Flint Jeremy J JJ Menon Kannan K Hansen Brian B Forder John J Blackband Stephen J SJ

NeuroImage 20200531

Since its first description and development in the late 20th century, diffusion magnetic resonance imaging (dMRI) has proven useful in describing the microstructural details of biological tissues. Signal generated from the protons of water molecules undergoing Brownian motion produces contrast based on the varied diffusivity of tissue types. Images employing diffusion contrast were first used to describe the diffusion characteristics of tissues, later used to describe the fiber orientations of w ...[more]

PMID: 32492508

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Project description:With its unparalleled ability to safely generate high-contrast images of soft tissues, magnetic resonance imaging (MRI) has remained at the forefront of diagnostic clinical medicine. Unfortunately due to resolution limitations, clinical scans are most useful for detecting macroscopic structural changes associated with a small number of pathologies. Moreover, due to a longstanding inability to directly observe magnetic resonance (MR) signal behavior at the cellular level, such information is poorly characterized and generally must be inferred. With the advent of the MR microscope in 1986 came the ability to measure MR signal properties of theretofore unobservable tissue structures. Recently, further improvements in hardware technology have made possible the ability to visualize mammalian cellular structure. In the current study, we expand upon previous work by imaging the neuronal cell bodies and processes of human and porcine ?-motor neurons. Complimentary imaging studies are conducted in pig tissue in order to demonstrate qualitative similarities to human samples. Also, apparent diffusion coefficient (ADC) maps were generated inside porcine ?-motor neuron cell bodies and portions of their largest processes (mean=1.7 ± 0.5 ?m²/ms based on 53 pixels) as well as in areas containing a mixture of extracellular space, microvasculature, and neuropil (0.59 ± 0.37 ?m²/ms based on 33 pixels). Three-dimensional reconstruction of MR images containing ?-motor neurons shows the spatial arrangement of neuronal projections between adjacent cells. Such advancements in imaging portend the ability to construct accurate models of MR signal behavior based on direct observation and measurement of the components which comprise functional tissues. These tools would not only be useful for improving our interpretation of macroscopic MRI performed in the clinic, but they could potentially be used to develop new methods of differential diagnosis to aid in the early detection of a multitude of neuropathologies.

Project description:IntroductionCardiovascular magnetic resonance (CMR)-guided cardiac catheterization is becoming more widespread due to the ability to acquire both functional CMR measurements and diagnostic catheterization data without exposing patients to ionizing radiation. However, the real-time imaging sequences used for catheter guidance during these procedures are limited in resolution and the anatomical detail they can provide. In this study, we propose a passive catheter tracking approach which simultaneously improves catheter tracking and visualization of the anatomy.Methods60 patients with congenital heart disease underwent CMR-guided cardiac catheterization on a 1.5T CMR scanner (Ingenia, Philips Healthcare, Best the Netherlands) using the Philips iSuite system. The proposed T1-overlay technique uses a commercially available heavily T1-weighted sequence to image the catheter, and overlays it on a high-resolution 3D dataset within iSuite in real-time. Suppressed tissue in the real-time images enables the use of a thick imaging slab to assist in tracking of the catheter. Improvement in catheter visualization time was compared between T1-overlay and the conventional invasive CMR (iCMR) balanced steady state free precession (bSSFP) sequence. This technique also enabled selective angiography visualization for real-time evaluation of blood flow dynamics (such as pulmonary transit time), similar to direct contrast injection under standard fluoroscopy. Estimates of pulmonary transit time using iCMR were validated using x-ray fluoroscopy in 16 patients.ResultsThe T1-overlay approach significantly increased the time that the catheter tip was kept in view by the technologist compared to the bSSFP sequence conventionally used for iCMR. The resulting images received higher ratings for blood/balloon contrast, anatomy visualization, and overall suitability for iCMR guidance by three cardiologists. iCMR selective angiography using T1-overlay also provided accurate estimates of pulmonary transit time that agreed well with x-ray fluoroscopy.ConclusionWe demonstrate a new passive catheter tracking technique using the iSuite platform that improves visualization of the catheter and cardiac anatomy. These improvements significantly increase the time that the catheter tip is seen throughout the procedure. We also demonstrate the feasibility of iCMR selective angiography for the measurement of pulmonary transit time.

Project description:Noradrenaline is a neurotransmitter involved in general arousal, selective attention, memory, inflammation, and neurodegeneration. The purpose of this work was to delineate noradrenergic neurons in vivo by T1-weighted MRI with magnetization transfer (MT). In the brainstem of human and mice, MRI identified the locus coeruleus, dorsal motor vagus nucleus, and nucleus tractus solitarius. Given (1) the long T1 and low magnetization transfer ratio for the noradrenergic cell groups compared to other gray matter, (2) significant correlation between MT MRI signal intensity and proton density, and (3) no correlation between magnetization transfer ratio (or R1) and iron, copper, or manganese in human brain, the high MRI signal of the noradrenergic neurons must be attributed to abundant water protons interacting with any T1-shortening paramagnetic ions in active cells rather than to specific T1-shortening molecules. The absence of a high MRI signal from the locus coeruleus of Ear2(-/-) mice lacking noradrenergic neurons confirms that cell bodies of noradrenergic neurons are the source of the bright MRI appearance. The observation of this high signal in DBH(-/-) mice, in 3-week-old mice, and in mice under hyperoxia/hypercapnia/hypoxia together with the general absence of neuromelanin (NM) in noradrenergic neurons of young rodents further excludes that it is due to NM, dopamine β-hydroxylase, their binding to paramagnetic ions, blood inflow, or hemoglobin. Instead, these findings indicate a high density of water protons whose T1 is shortened by paramagnetic ions as the relevant source of the high MRI signal. In the brain of APP/PS1/Ear2(-/-) mice, a transgenic model of Alzheimer's disease, MRI detected noradrenergic neuron loss in the locus coeruleus. Proton magnetic resonance spectroscopy revealed that a 60-75% reduction of noradrenaline is responsible for a reduction of N-acetylaspartate and glutamate in the hippocampus as well as for a shortening of the water proton T2 in the frontal cortex. These results suggest that a concurrent shortage of noradrenaline in Alzheimer's disease accelerates pathologic processes such as inflammation and neuron loss.

Project description:Can 1H Magnetic Resonance Spectroscopy (MRS) be used to obtain information about the molecules and metabolites in live human spermatozoa?Percoll-based density gradient centrifugation (DGC) followed by a further two washing steps, yielded enough sperm with minimal contamination (<0.01%) from seminal fluid to permit effective MRS which detected significant differences (P < 0.05) in the choline/glycerophosphocholine (GPC), lipid and lactate regions of the 1H MRS spectrum between sperm in the pellet and those from the 40%/80% interface.Current methods to examine sperm are either limited in their value (e.g. semen analysis) or are destructive (e.g. immunohistochemistry, sperm DNA testing). A few studies have previously used MRS to examine sperm, but these have either looked at seminal plasma from men with different ejaculate qualities or at the molecules present in pooled samples of lyophilized sperm.Sperm suspended in phosphate buffered saline (PBS) at 37°C were examined by 1H MRS scanning using a 1H excitation-sculpting solvent suppression sequence after recovery from fresh ejaculates by one of three different methods: (i) simple centrifugation; (ii) DGC with one wash; or (iii) DGC with two washes. In the case of DGC, sperm were collected both from the pellet ('80%' sperm) and the 40/80 interface ('40%' sperm). Spectrum processing was carried out using custom Matlab scripts to determine; the degree of seminal plasma/Percoll contamination, the minimum sperm concentration for 1H MRS detection and differences between the 1H MRS spectra of '40%' and '80%' sperm.DGC with two washes minimized the 1H MRS peak intensity for both seminal plasma and Percoll/PBS solution contamination while retaining sperm specific peaks. For the MRS scanner used in this study, the minimum sperm concentration required to produce a choline/GPC 1H MRS peak greater than 3:1 signal to noise ratio (SNR) was estimated at ~3 × 106/ml. The choline/GPC and lactate/lipid regions of the 1H spectrum were significantly different by two-way ANOVA analysis (P < 0.0001; n = 20). ROC curve analysis of these region showed significant ability to distinguish between the two sperm populations: choline/GPC ROC AUC = 0.65-0.67, lactate/lipid ROC AUC = 0.86-0.87.Only 3-4 semen samples were used to assess the efficacy of each sperm washing protocol that were examined. The estimated minimum sperm concentration required for MRS is specific to the hardware used in our study and may be different in other spectrometers. Spectrum binning is a low resolution analysis method that sums MRS peaks within a chemical shift range. This can obscure the identity of which metabolite(s) are responsible for differences between sperm populations. Further work is required to determine the relative contribution of somatic cells to the MRS spectrum from the '40%' and '80%' sperm.1H MRS can provide information about the molecules present in live human sperm and may therefore permit the study of the underlying functional biology or metabolomics of live sperm. Given the relatively low concentration of sperm required to obtain a suitable MRS signal (~3 × 106/ml), this could be carried out on sperm from men with oligo-, astheno- or teratozoospermia. This may lead to the development of new diagnostic tests or ultimately novel treatments for male factor infertility.This work was supported by the Medical Research Council Grant MR/M010473/1. The authors declare no conflicts of interest.

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Visualization of live, mammalian neurons during Kainate-infusion using magnetic resonance microscopy.

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Visualization of live, mammalian neurons during Kainate-infusion using magnetic resonance microscopy.

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