Microstructural imaging of the human brain with a 'super-scanner': 10 key advantages of ultra-strong gradients for diffusion MRI

The key component of a microstructural diffusion MRI 'super-scanner' is a dedicated high-strength gradient system that enables stronger diffusion weightings per unit time compared to conventional gradient designs. This can, in turn, drastically shorten the time needed for diffusion encoding, increase the signal-to-noise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the UK National Facility for In Vivo MR Imaging of Human Tissue Microstructure, an initiative to establish a shared 300 mT/m-gradient facility amongst the microstructural imaging community, describes ten advantages of ultra-strong gradients for microstructural imaging. Specifically, we will discuss how the increase of the accessible measurement space compared to a lower-gradient systems (in terms of Δ, b-value, and TE) can accelerate developments in the areas of 1) axon diameter distribution mapping; 2) microstructural parameter estimation; 3) mapping micro-vs macroscopic anisotropy features with gradient waveforms beyond a single pair of pulsed-gradients; 4) multi-contrast experiments, e.g. diffusion-relaxometry; 5) tractography and high-resolution imaging in vivo and 6) post mortem; 7) diffusion-weighted spectroscopy of metabolites other than water; 8) tumour characterisation; 9) functional diffusion MRI; and 10) quality enhancement of images acquired on lower-gradient systems. We finally discuss practical barriers in the use of ultra-strong gradients, and provide an outlook on the next generation of 'super-scanners'

Studying neuroanatomy using MRI

The study of neuroanatomy using imaging enables key insights into how our brains function, are shaped by genes and environment, and change with development, aging, and disease. Developments in MRI acquisition, image processing, and data modelling have been key to these advances. However, MRI provides an indirect measurement of the biological signals we aim to investigate. Thus, artifacts and key questions of correct interpretation can confound the readouts provided by anatomical MRI. In this review we provide an overview of the methods for measuring macro- and mesoscopic structure and inferring microstructural properties; we also describe key artefacts and confounds that can lead to incorrect conclusions. Ultimately, we believe that, though methods need to improve and caution is required in its interpretation, structural MRI continues to have great promise in furthering our understanding of how the brain works

Resolving bundle-specific intra-axonal T₂ values within a voxel using diffusion-relaxation tract-based estimation.

At the typical spatial resolution of MRI in the human brain, approximately 60-90% of voxels contain multiple fiber populations. Quantifying microstructural properties of distinct fiber populations within a voxel is therefore challenging but necessary. While progress has been made for diffusion and T <sub>1</sub> -relaxation properties, how to resolve intra-voxel T <sub>2</sub> heterogeneity remains an open question. Here a novel framework, named COMMIT-T <sub>2</sub> , is proposed that uses tractography-based spatial regularization with diffusion-relaxometry data to estimate multiple intra-axonal T <sub>2</sub> values within a voxel. Unlike previously-proposed voxel-based T <sub>2</sub> estimation methods, which (when applied in white matter) implicitly assume just one fiber bundle in the voxel or the same T <sub>2</sub> for all bundles in the voxel, COMMIT-T <sub>2</sub> can recover specific T <sub>2</sub> values for each unique fiber population passing through the voxel. In this approach, the number of recovered unique T <sub>2</sub> values is not determined by a number of model parameters set a priori, but rather by the number of tractography-reconstructed streamlines passing through the voxel. Proof-of-concept is provided in silico and in vivo, including a demonstration that distinct tract-specific T <sub>2</sub> profiles can be recovered even in the three-way crossing of the corpus callosum, arcuate fasciculus, and corticospinal tract. We demonstrate the favourable performance of COMMIT-T <sub>2</sub> compared to that of voxelwise approaches for mapping intra-axonal T <sub>2</sub> exploiting diffusion, including a direction-averaged method and AMICO-T <sub>2</sub> , a new extension to the previously-proposed Accelerated Microstructure Imaging via Convex Optimization (AMICO) framework

Spreading depolarizations increase delayed brain injury in a rat model of subarachnoid hemorrhage

Paroxysmal Cerebral Disorder

Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA gyrase B

A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC <sub>50</sub> < 1 nM and Mtb MIC < 0.1 muM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis. 2013 American Chemical Societ