In vivo Correlation Tensor MRI reveals microscopic kurtosis in the human brain on a clinical 3T scanner

Diffusion MRI (dMRI) has become one of the most important imaging modalities for noninvasively probing tissue microstructure. Diffusional Kurtosis MRI (DKI) quantifies the degree of non-Gaussian diffusion, which in turn has been shown to increase sensitivity towards, e.g., disease and orientation mapping in neural tissue. However, the specificity of DKI is limited as different sources can contribute to the total intravoxel diffusional kurtosis, including: variance in diffusion tensor magnitudes (K_iso), variance due to diffusion anisotropy (K_aniso), and microscopic kurtosis (μK) related to restricted diffusion, microstructural disorder, and/or exchange. Interestingly, μK is typically ignored in diffusion MRI signal modelling as it is assumed to be negligible in neural tissues. However, recently, Correlation Tensor MRI (CTI) based on Double-Diffusion-Encoding (DDE) was introduced for kurtosis source separation, revealing non negligible μK in preclinical imaging. Here, we implemented CTI for the first time on a clinical 3T scanner and investigated the sources of total kurtosis in healthy subjects. A robust framework for kurtosis source separation in humans is introduced, followed by estimation of μK (and the other kurtosis sources) in the healthy brain. Using this clinical CTI approach, we find that μK significantly contributes to total diffusional kurtosis both in grey and white matter tissue but, as expected, not in the ventricles. The first μK maps of the human brain are presented, revealing that the spatial distribution of μK provides a unique source of contrast, appearing different from isotropic and anisotropic kurtosis counterparts. Moreover, group average templates of these kurtosis sources have been generated for the first time, which corroborated our findings at the underlying individual-level maps. We further show that the common practice of ignoring μK and assuming the multiple Gaussian component approximation for kurtosis source estimation introduces significant bias in the estimation of other kurtosis sources and, perhaps even worse, compromises their interpretation. Finally, a twofold acceleration of CTI is discussed in the context of potential future clinical applications. We conclude that CTI has much potential for future in vivo microstructural characterizations in healthy and pathological tissue.