Diffusion-time dependence of diffusional kurtosis in the mouse brain

Purpose: To investigate diffusion-time dependency of diffusional kurtosis in the mouse brain using pulsed-gradient spin-echo (PGSE) and oscillating-gradient spin-echo (OGSE) sequences. Methods: 3D PGSE and OGSE kurtosis tensor data were acquired from ex vivo brains of adult, cuprizone-treated, and age-matched control mice with diffusion-time (t_D) ~ 20 ms and frequency (f) = 70 Hz, respectively. Further, 2D acquisitions were performed at multiple times/frequencies ranging from f = 140 Hz to t_D = 30 ms with b-values up to 4000 s/mm². Monte Carlo simulations were used to investigate the coupled effects of varying restriction size and permeability on time/frequency-dependence of kurtosis with both diffusion-encoding schemes. Simulations and experiments were further performed to investigate the effect of varying number of cycles in OGSE waveforms. Results: Kurtosis and diffusivity maps exhibited significant region-specific changes with diffusion time/frequency across both gray and white matter areas. PGSE- and OGSE-based kurtosis maps showed reversed contrast between gray matter regions in the cerebellar and cerebral cortex. Localized time/frequency-dependent changes in kurtosis tensor metrics were found in the splenium of the corpus callosum in cuprizone-treated mouse brains, corresponding to regional demyelination seen with histological assessment. Monte Carlo simulations showed that kurtosis estimates with pulsed- and oscillating-gradient waveforms differ in their sensitivity to exchange. Both simulations and experiments showed dependence of kurtosis on number of cycles in OGSE waveforms for non-zero permeability. Conclusion: The results show significant time/frequency-dependency of diffusional kurtosis in the mouse brain, which can provide sensitivity to probe intrinsic cellular heterogeneity and pathological alterations in gray and white matter.