In vivo observation and biophysical interpretation of time-dependent diffusion in human cortical gray matter

The dependence of the diffusion MRI signal on the diffusion time t is a hallmark of tissue microstructure at the scale of the diffusion length. Here we measure the time-dependence of the mean diffusivity D(t) and mean kurtosis K(t) in cortical gray matter and in 25 ​gray matter sub-regions, in 10 healthy subjects. Significant diffusivity and kurtosis time-dependence is observed for t=21.2-100 ​ms, and is characterized by a power-law tail ∼t^-ϑ with dynamical exponent ϑ. To interpret our measurements, we systematize the relevant scenarios and mechanisms for diffusion time-dependence in the brain. Using the effective medium theory formalism, we derive an exact relation between the power-law tails in D(t) and K(t). The estimated dynamical exponent ϑ≃1/2 in both D(t) and K(t) is consistent with one-dimensional diffusion in the presence of randomly positioned restrictions along neurites. We analyze the short-range disordered statistics of synapses on axon collaterals in the cortex, and perform one-dimensional Monte Carlo simulations of diffusion restricted by permeable barriers with a similar randomness in their placement, to confirm the ϑ=1/2 exponent. In contrast, the Kärger model of exchange is less consistent with the data since it does not capture the diffusivity time-dependence, and the estimated exchange time from K(t) falls below our measured t-range. Although we cannot exclude exchange as a contributing factor, we argue that structural disorder along neurites is mainly responsible for the observed time-dependence of diffusivity and kurtosis. Our observation and theoretical interpretation of the t^-1/2 tail in D(t) and K(t) altogether establish the sensitivity of a macroscopic MRI signal to micrometer-scale structural heterogeneities along neurites in human gray matter in vivo.