The human hippocampus plays a key role in memory management and is one of the first structures affected by Alzheimer's disease. Ultra-high magnetic resonance imaging provides access to its inner structure in vivo. However, gradient limitations on clinical systems hinder access to its inner connectivity and microstructure. A major target of this paper is the demonstration of diffusion MRI potential, using ultra-high field (11.7 T) and strong gradients (750 mT/m), to reveal the extra-and intrahippocampal connectivity in addition to its microstructure. To this purpose, a multiple-shell diffusion-weighted acquisition protocol was developed to reach an ultra-high spatio-angular resolution with a good signal-to-noise ratio. The MRI data set was analyzed using analytical Q-Ball Imaging, Diffusion Tensor Imaging (DTI), and Neurite Orientation Dispersion and Density Imaging models. High Angular Resolution Diffusion Imaging estimates allowed us to obtain an accurate tractography resolving more complex fiber architecture than DTI models, and subsequently provided a map of the cross-regional connectivity. The neurite density was akin to that found in the histological literature, revealing the three hippocampal layers. Moreover, a gradient of connectivity and neurite density was observed between the anterior and the posterior part of the hippocampus. These results demonstrate that ex vivo ultra-high field/ultra-high gradients diffusion-weighted MRI allows the mapping of the inner connectivity of the human hippocampus, its microstructure, and to accurately reconstruct elements of the polysynaptic intra-hippocampal pathway using fiber tractography techniques at very high spatial/angular resolutions.

White matter is composed of irregularly packed axons leading to a structural disorder in the extra-axonal space. Diffusion MRI experiments using oscillating gradient spin echo sequences have shown that the diffusivity transverse to axons in this extra-axonal space is dependent on the frequency of the employed sequence. In this study, we observe the same frequency-dependence using 3D simulations of the diffusion process in disordered media. We design a novel white matter numerical phantom generation algorithm which constructs biomimicking geometric configurations with few design parameters, and enables to control the level of disorder of the generated phantoms. The influence of various geometrical parameters present in white matter, such as global angular dispersion, tortuosity, presence of Ranvier nodes, beading, on the extra-cellular perpendicular diffusivity frequency dependence was investigated by simulating the diffusion process in numerical phantoms of increasing complexity and fitting the resulting simulated diffusion MR signal attenuation with an adequate analytical model designed for trapezoidal OGSE sequences.This work suggests that angular dispersion and especially beading have non-negligible effects on this extracellular diffusion metrics that may be measured using standard OGSE DW-MRI clinical protocols.