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-tonoise ratio, and facilitate measurements at shorter diffusion times. This review, written from the perspective of the National Facility for In Vivo MR Imaging of Human Tissue
... ture, 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 ∆, bvalue, 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. diffusionrelaxometry; 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 'superscanners'. then discuss practical challenges in making use of such as system, including issues of safety and engineering aspects, attempt to highlight which limits are fundamental, and which just require engineering. The main advantage is, of course, in providing a higher q-value/shorter echo time (TE) for a given b-value, and a higher signal-to-noise ratio (SNR) per unit b-value (see Figure 1a ). Shorter diffusion time acquisitions also become more practical as higher b-values can be achieved, and a wider range of b-values can be maintained across all diffusion times (∆) (Figure 1b) . FIGURE 1: Increase of the accessible parameter space with ultra-strong gradients. (a) b-value vs minimum achievable echo time (TE) for different maximum gradient amplitudes of 40 mT/m, 80 mT/m and 300 mT/m (see also Setsompop et al., 2013). For each point, the colour coding gives the achieved ∆ − / [ms] (colour coding according to ∆ results in a similar figure with the colourbar ranging from 19 ms -97 ms). These curves were obtained by simulation on the system with a Stejskal-Tanner EPI sequence, Voxel size = [2.5 2.5 2.5] mm, no partial Fourier, GRAPPA = 2, Multiband = 1. (b) PGSE b-value (colours) plotted as a function of G and ∆ for Gmax = 80 mT/m (left two panels) and 300 mT/m (right panel). Differences in rise times for Gmax = 80 and 300 mT/m (0.4 ms THE PROMISE One of the fundamental limits to axon-diameter estimation is the so-called "resolution limit" of the diffusion experiment. The diffusion-weighted MR signal is sensitive only to a window of restriction lengths and the bounds of that window depend strongly on the available gradient strength. Moreover, most axon diameters lie below the lower bound of the window (the resolution limit) given the available gradient strength in most currently available MRI scanners. Dyrby et al. (Dyrby, Søgaard, Hall, Ptito, & Alexander, 2012; Dyrby et al., 2012) demonstrate empirically the advantages of increasing gradient strength in axon diameter mapping using simulations and ex vivo measurements on a monkey corpus callosum using a small-bore scanner with 400mT/m gradients (see Figure 2c) . Drobnjak et al. (Drobnjak, Zhang, Ianuş, Kaden, & Alexander, 2016) identified the resolution limit numerically for combinations of pulsed gradient spin echo (PGSE) and oscillating gradient spin echo (OGSE) measurements, and showed that in the idealised experiment where the gradients are perpendicular to straight, parallel, impermeable cylinders, the standard PGSE experiment gives the greatest sensitivity and that the resolution limit on axon diameter is in the range 4.5-7um (depending on available SNR) with 60mT/m, but reduces to 2-3um with 300mT/m. In the more realistic situation for brain tissue, where the magnetic field gradient is not quite perpendicular to the fibres and/or the fibres have dispersed orientations, the resolution limit increases, although using OGSE instead of PGSE mitigates this increase to some extent. For example, with the gradient 10 degrees from perpendicular, or with moderate orientational dispersion (characterised by a Watson distribution with a dispersion parameter of 16), using OGSE, the resolution limit increases by about 1um (see Figure 2d ).