Axon diameters and myelin content modulate microscopic fractional anisotropy at short diffusion times in fixed rat spinal cord

Mapping tissue microstructure accurately and noninvasively is one of the frontiers of biomedical imaging. Diffusion Magnetic Resonance Imaging (MRI) is at the forefront of such efforts, as it is capable of reporting on microscopic structures orders of magnitude smaller than the voxel size by probing restricted diffusion. Double Diffusion Encoding (DDE) and Double Oscillating Diffusion Encoding (DODE) in particular, are highly promising for their ability to report on microscopic fractional anisotropy ({\mu}FA), a measure of the pore anisotropy in its own eigenframe, irrespective of orientation distribution. However, the underlying correlates of {\mu}FA have insofar not been studied. Here, we extract {\mu}FA from DDE and DODE measurements at ultrahigh magnetic field of 16.4T in the aim to probe fixed rat spinal cord microstructure. We further endeavor to correlate {\mu}FA with Myelin Water Fraction (MWF) derived from multiexponential T2 relaxometry, as well as with literature-based spatially varying axonal diameters. In addition, a simple new method is presented for extracting unbiased {\mu}FA from three measurements at different b-values. Our findings reveal strong anticorrelations between {\mu}FA (derived from DODE) and axon diameter in the distinct spinal cord tracts; a moderate correlation was also observed between {\mu}FA derived from DODE and MWF. These findings suggest that axonal membranes strongly modulate {\mu}FA, which - owing to its robustness towards orientation dispersion effects - reflects axon diameter much better than its typical FA counterpart. The {\mu}FA exhibited modulations when measured via oscillating or blocked gradients, suggesting selective probing of different parallel path lengths and providing insight into how those modulate {\mu}FA metrics. Our findings thus shed light into the underlying microstructural correlates of {\mu}FA and are (...

BOLD-fMRI in the mouse auditory pathway

The auditory pathway is widely distributed throughout the brain, and is perhaps one of the most interesting networks in the context of neuroplasticity. Accurate mapping of neural activity in the entire pathway, preferably noninvasively, and with high resolution, could be instrumental for understanding such longitudinal processes. Functional magnetic resonance imaging (fMRI) has clear advantages for such characterizations, as it is noninvasive, provides relatively high spatial resolution and lends itself for repetitive studies, albeit relying on an indirect neurovascular coupling to deliver its information. Indeed, fMRI has been previously used to characterize the auditory pathway in humans and in rats. In the mouse, however, the auditory pathway has insofar only been mapped using manganese-enhanced MRI. Here, we describe a novel setup specifically designed for high-resolution mapping of the mouse auditory pathway using high-field fMRI. Robust and consistent Blood-Oxygenation-Level-Dependent (BOLD) responses were documented along nearly the entire auditory pathway, from the cochlear nucleus (CN), through the superior olivary complex (SOC), nuclei of the lateral lemniscus (LL), inferior colliculus (IC) and the medial geniculate body (MGB). By contrast, clear BOLD responses were not observed in auditory cortex (AC) in this study. Diverse BOLD latencies were mapped ROI- and pixel-wise using coherence analysis, evidencing different averaged BOLD time courses in different auditory centers. Some degree of tonotopy was identified in the IC, SOC, and MGB in the pooled dataset though it could not be assessed per subject due to a lack of statistical power. Given the importance of the mouse model in plasticity studies, animal models, and optogenetics, and fMRI's potential to map dynamic responses to specific cues, this first fMRI study of the mouse auditory pathway paves the way for future (...

Effects of nongaussian diffusion on "isotropic diffusion measurements'': an ex-vivo microimaging and simulation study

Designing novel diffusion-weighted pulse sequences to probe tissue microstructure beyond the conventional Stejskal-Tanner family is currently of broad interest. One such technique, multidimensional diffusion MRI, has been recently proposed to afford model-free decomposition of diffusion signal kurtosis into terms originating from either ensemble variance of isotropic diffusivity or microscopic diffusion anisotropy. This ability rests on the assumption that diffusion can be described as a sum of multiple Gaussian compartments, but this is often not strictly fulfilled. The effects of nongaussian diffusion on single shot isotropic diffusion sequences were first considered in detail by de Swiet and Mitra in 1996. They showed theoretically that anisotropic compartments lead to anisotropic time dependence of the diffusion tensors, which causes the measured isotropic diffusivity to depend on gradient frame orientation. Here we show how such deviations from the multiple Gaussian compartments assumption conflates orientation dispersion with ensemble variance in isotropic diffusivity. Second, we consider additional contributions to the apparent variance in isotropic diffusivity arising due to intracompartmental kurtosis. These will likewise depend on gradient frame orientation. We illustrate the potential importance of these confounds with analytical expressions, numerical simulations in simple model geometries, and microimaging experiments in fixed spinal cord using isotropic diffusion encoding waveforms with 7.5 ms duration and 3000 mT/m maximum amplitude.Comment: 26 pages, 9 figures. Appearing in J. Magn. Reso