QUANTATITIVE STUDY OF WATER DYNAMICS IN BIOMIMETIC MODELS AND LIVING TISSUE BY NMR AND MRI: PERSPECTIVES ON DIRECT DETECTION NEURONAL ACTIVITY

Detection of neuronal activity noninvasively and in vivo is a desideratum in medicine and in neuroscience. Unfortunately, the widely used method of functional magnetic resonance imaging (fMRI) only indirectly assesses neuronal activity via its hemodynamic response; limiting its temporal and spatial accuracy. Recently, several new fMRI methods have been proposed to measure neuronal activity claiming to be more direct and accurate. However, these approaches have proved difficult to reproduce and are not widely applied mainly because of a dearth of “ground truth” experiments that convincingly establish the correlation between the magnetic resonance (MR) signals and the underlying neuronal activity. In addition, limited knowledge of water dynamics in living tissue restricts our understanding of the underlying biophysical sources of these candidate fMRI signals. To address the first problem, we developed a novel test system to assess and validate fMRI methods, in which real-time fluorescent intracellular calcium images and MR recording were simultaneously acquired on organotypic rat-cortex cultures without hemodynamic confounds. This experimental design enables direct correlation of the candidate functional MR signals with optical indicia of the underlying neuronal activity. Within this test bed, MR signals with contrasts from water relaxation times, diffusion, and proton density were tested. Diffusion MR was the only one shown to be sensitive to the pathological condition of hyperexcitability, e.g., such as those seen in epilepsy. However, these MR signals do not appear to be sensitive or specific enough to detect and follow normal neuronal activity. Efforts were made toward improving our understanding of the water dynamics in living tissue. First, water diffusivities and relaxation times in a biomimetic model were measured and quantitatively studied using different biophysical-based mathematical models. Second, we developed and applied a rapid 2D diffusion/relaxation spectral MR method, to better characterize the heterogeneous nature of tissue water. While the present study is still far from providing a complete picture of water dynamics in living tissues, it provides novel tools for advancing our understanding of the possibilities and limits of detecting neuronal activity via MR in the future, as well as providing a reproducible and reliable way to assess and validate fMRI methods

Age- and time-of-day dependence of glymphatic function in the human brain measured via two diffusion MRI methods

Advanced age, accompanied by impaired glymphatic function, is a key risk factor for many neurodegenerative diseases. To study age-related differences in the human glymphatic system, we measured the influx and efflux activities of the glymphatic system via two non-invasive diffusion magnetic resonance imaging (MRI) methods, ultra-long echo time and low-b diffusion tensor imaging (DTIlow–b) measuring the subarachnoid space (SAS) flow along the middle cerebral artery and DTI analysis along the perivascular space (DTI-ALPS) along medullary veins in 22 healthy volunteers (aged 21–75 years). We first evaluated the circadian rhythm dependence of the glymphatic activity by repeating the MRI measurements at five time points from 8:00 to 23:00 and found no time-of-day dependence in the awake state under the current sensitivity of MRI measurements. Further test–retest analysis demonstrated high repeatability of both diffusion MRI measurements, suggesting their reliability. Additionally, the influx rate of the glymphatic system was significantly higher in participants aged >45 years than in participants aged 21–38, while the efflux rate was significantly lower in those aged >45 years. The mismatched influx and efflux activities in the glymphatic system might be due to age-related changes in arterial pulsation and aquaporin-4 polarization

Walking With the ISMRM in the Footprints of Our MR History

The International Society for Magnetic Resonance in Medicine (ISMRM) has undoubtedly played a central role in helping shape our field. In particular, the annual meetings have been an avenue of choice for presenting new MR methods, tools, and applications of aspects of our field that have greatly impacted and transformed how MR is used today, and those abstracts have become “classic” contributions to our field. In 1994, the ISMRM (or SMR, as it was named at the time) was formed from the joining of the Society for Magnetic Resonance in Medicine (SMRM) and the Society for Magnetic Resonance Imaging (SMRI), which originated in 1982. In those early years, MR was a nascent technology and many of the sequences, analysis tools, and hardware applications we take for granted today had not yet been conceived. Now, as a celebration of the 40th anniversary of these annual meetings, we walk in the “footprints” of the ISMRM and its predecessor Societies: we look back at some of the classic abstracts presented at the annual meetings, reflect on this long history with some of its early members, and report on the Special Session held to celebrate the occasion at the 2022 Annual Meeting in London

Recommendations and guidelines from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 1 -- In vivo small-animal imaging

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the data. This work aims to serve as a reference, presenting selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. In each section, we also highlight areas for which no guidelines exist (and why), and where future work should focus. We first describe the value that small animal imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss how they are appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, imaging sequences and data processing, including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge.Comment: 69 pages, 6 figures, 1 tabl

Data inversion of multi-dimensional magnetic resonance in porous media

Since its inception in the 1970s, multi-dimensional magnetic resonance (MR) has emerged as a powerful tool for non-invasive investigations of structures and molecular interactions. MR spectroscopy beyond one dimension allows the study of the correlation, exchange processes, and separation of overlapping spectral information. The multi-dimensional concept has been re-implemented over the last two decades to explore molecular motion and spin dynamics in porous media. Apart from Fourier transform, methods have been developed for processing the multi-dimensional time-domain data, identifying the fluid components, and estimating pore surface permeability via joint relaxation and diffusion spectra. Through the resolution of spectroscopic signals with spatial encoding gradients, multi-dimensional MR imaging has been widely used to investigate the microscopic environment of living tissues and distinguish diseases. Signals in each voxel are usually expressed as multi-exponential decay, representing microstructures or environments along multiple pore scales. The separation of contributions from different environments is a common ill-posed problem, which can be resolved numerically. Moreover, the inversion methods and experimental parameters determine the resolution of multi-dimensional spectra. This paper reviews the algorithms that have been proposed to process multi-dimensional MR datasets in different scenarios. Detailed information at the microscopic level, such as tissue components, fluid types and food structures in multi-disciplinary sciences, could be revealed through multi-dimensional MR

On the sampling strategies and models for measuring diffusion exchange with a double diffusion encoding sequence

Water exchange between the different compartments of a heterogeneous specimen can be characterized via diffusion magnetic resonance imaging (dMRI). Many analysis frameworks using dMRI data have been proposed to describe exchange, often using a double diffusion encoding (DDE) stimulated echo sequence. Techniques such as diffusion exchange weighted imaging (DEWI) and the filter exchange and rapid exchange models, use a specific subset of the full space DDE signal. In this work, a general representation of the DDE signal was employed with different sampling schemes (namely constant �1, diagonal and anti-diagonal) from the data reduction models to estimate exchange. A near-uniform sampling scheme was proposed and compared with the other sampling schemes. The filter exchange and rapid exchange models were also applied to estimate exchange with their own subsampling schemes. These subsampling schemes and models were compared on both simulated data and experimental data acquired with a benchtop MR scanner. In synthetic data, the diagonal and near-uniform sampling schemes performed the best due to the consistency of their estimates with the ground truth. In experimental data, the shifted diagonal and near-uniform sampling schemes outperformed the others, yielding the most consistent estimates with the full space estimation. The results suggest the feasibility of measuring exchange using a general representation of the DDE signal along with variable sampling schemes. In future studies, algorithms could be further developed for the optimization of sampling schemes, as well as incorporating additional properties, such as geometry and diffusion anisotropy, into exchange frameworks.Funding agencies:This research was funded by the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), and the Swedish Research Council (Dnr 2022–04715).</p

The direction-dependence of apparent water exchange rate in human white matter

Transmembrane water exchange is a potential biomarker in the diagnosis and understanding of cancers, brain disorders, and other diseases. Filter-exchange imaging (FEXI), a special case of diffusion exchange spectroscopy adapted for clinical applications, has the potential to reveal different physiological water exchange processes. However, it is still controversial whether modulating the diffusion encoding gradient direction can affect the apparent exchange rate (AXR) measurements of FEXI in white matter (WM) where water diffusion shows strong anisotropy. In this study, we explored the diffusion-encoding direction dependence of FEXI in human brain white matter by performing FEXI with 20 diffusion-encoding directions on a clinical 3T scanner in-vivo. The results show that the AXR values measured when the gradients are perpendicular to the fiber orientation (0.77 +/- 0.13 s - 1 , mean +/- standard deviation of all the subjects) are significantly larger than the AXR estimates when the gradients are parallel to the fiber orientation (0.33 +/- 0.14 s - 1 , p &amp;lt; 0.001) in WM voxels with coherently-orientated fibers. In addition, no significant correlation is found between AXRs measured along these two directions, indicating that they are measuring different water exchange processes. Whats more, only the perpendicular AXR rather than the parallel AXR shows dependence on axonal diameter, indicating that the perpendicular AXR might reflect transmembrane water exchange between intra-axonal and extra-cellular spaces. Further finite difference (FD) simulations having three water compartments (intra-axonal, intra-glial, and extra-cellular spaces) to mimic WM micro-environments also suggest that the perpendicular AXR is more sensitive to the axonal water transmembrane exchange than parallel AXR. Taken together, our results show that AXR measured along different directions could be utilized to probe different water exchange processes in WM.Funding Agencies|National Natural Science Foundation of China (NSFC)National Natural Science Foundation of China (NSFC) [81873894, 82111530201]; Natural Science Foundation of Zhejiang Province, ChinaNatural Science Foundation of Zhejiang Province [LR20H180001]; MOE Frontier Science Center for Brain Science &amp; Brain-Machine Integration, Zhejiang University; Swedish Foundation for International Cooperation in Research and Higher Education (STINT)</p