Investigating apparent differences between standard DKI and axisymmetric DKI and its consequences for biophysical parameter estimates.

PURPOSE: The purpose of the study is to identify differences between axisymmetric diffusion kurtosis imaging (DKI) and standard DKI, their consequences for biophysical parameter estimates, and the protocol choice influence on parameter estimation. METHODS: Noise-free and noisy, synthetic diffusion MRI human brain data is simulated using standard DKI for a standard and the fast "199" acquisition protocol. First the noise-free "baseline" difference between both DKI models is estimated and the influence of fiber complexity is investigated. Noisy data is used to establish the signal-to-noise ratio at which the baseline difference exceeds noise variability. The influence of protocol choices and denoising is investigated. The five axisymmetric DKI tensor metrics (AxTM), the parallel and perpendicular diffusivity and kurtosis and mean of the kurtosis tensor are used to compare both DKI models. Additionally, the baseline difference is also estimated for the five parameters of the WMTI-Watson model. RESULTS: The parallel and perpendicular kurtosis and all of the WMTI-Watson parameters had large baseline differences. Using a Westin or FA mask reduced the number of voxels with large baseline difference, that is, by selecting voxels with less complex fibers. For the noisy data, precision was worsened by the fast "199" protocol but adaptive denoising can help counteract these effects. CONCLUSION: For the diffusivities and mean of the kurtosis tensor, axisymmetric DKI with a standard protocol delivers similar results as standard DKI. Fiber complexity is one main driver of the baseline differences. Using the "199" protocol worsens precision in noisy data but adaptive denoising mitigates these effects.

Insights and improvements in correspondence between axonal volume fraction measured with diffusion-weighted MRI and electron microscopy.

Biophysical diffusion-weighted imaging (DWI) models are increasingly used in neuroscience to estimate the axonal water fraction ( f AW ), which in turn is key for noninvasive estimation of the axonal volume fraction ( f A ). These models require thorough validation by comparison with a reference method, for example, electron microscopy (EM). While EM studies often neglect the unmyelinated axons and solely report the fraction of myelinated axons, in DWI both myelinated and unmyelinated axons contribute to the DWI signal. However, DWI models often include simplifications, for example, the neglect of differences in the compartmental relaxation times or fixed diffusivities, which in turn might affect the estimation of f AW . We investigate whether linear calibration parameters (scaling and offset) can improve the comparability between EM- and DWI-based metrics of f A . To this end, we (a) used six DWI models based on the so-called standard model of white matter (WM), including two models with fixed compartmental diffusivities (e.g., neurite orientation dispersion and density imaging, NODDI) and four models that fitted the compartmental diffusivities (e.g., white matter tract integrity, WMTI), and (b) used a multimodal data set including ex vivo diffusion DWI and EM data in mice with a broad dynamic range of fibre volume metrics. We demonstrated that the offset is associated with the volume fraction of unmyelinated axons and the scaling factor is associated with different compartmental T 2 and can substantially enhance the comparability between EM- and DWI-based metrics of f A . We found that DWI models that fitted compartmental diffusivities provided the most accurate estimates of the EM-based f A . Finally, we introduced a more efficient hybrid calibration approach, where only the offset is estimated but the scaling is fixed to a theoretically predicted value. Using this approach, a similar one-to-one correspondence to EM was achieved for WMTI. The method presented can pave the way for use of validated DWI-based models in clinical research and neuroscience.

Towards a representative reference for MRI-based human axon radius assessment using light microscopy.

Non-invasive assessment of axon radii via MRI bears great potential for clinical and neuroscience research as it is a main determinant of the neuronal conduction velocity. However, there is a lack of representative histological reference data at the scale of the cross-section of MRI voxels for validating the MRI-visible, effective radius (reff). Because the current gold standard stems from neuroanatomical studies designed to estimate the bulk-determined arithmetic mean radius (rarith) on small ensembles of axons, it is unsuited to estimate the tail-weighted reff. We propose CNN-based segmentation on high-resolution, large-scale light microscopy (lsLM) data to generate a representative reference for reff. In a human corpus callosum, we assessed estimation accuracy and bias of rarith and reff. Furthermore, we investigated whether mapping anatomy-related variation of rarith and reff is confounded by low-frequency variation of the image intensity, e.g., due to staining heterogeneity. Finally, we analyzed the error due to outstandingly large axons in reff. Compared to rarith, reff was estimated with higher accuracy (maximum normalized-root-mean-square-error of reff: 8.5 %; rarith: 19.5 %) and lower bias (maximum absolute normalized-mean-bias-error of reff: 4.8 %; rarith: 13.4 %). While rarith was confounded by variation of the image intensity, variation of reff seemed anatomy-related. The largest axons contributed between 0.8 % and 2.9 % to reff. In conclusion, the proposed method is a step towards representatively estimating reff at MRI voxel resolution. Further investigations are required to assess generalization to other brains and brain areas with different axon radii distributions.