Time-Dependent Diffusion MRI in Cancer: Tissue Modeling and Applications

In diffusion weighted imaging (DWI), the apparent diffusion coefficient (ADC) has been recognized as a useful and sensitive surrogate for cell density, paving the way for non-invasive tumor staging, and characterization of treatment efficacy in cancer. However, microstructural parameters, such as cell size, density and/or compartmental diffusivities affect diffusion in various fashions, making of conventional DWI a sensitive but non-specific probe into changes happening at cellular level. Alternatively, tissue complexity can be probed and quantified using the time dependence of diffusion metrics, sometimes also referred to as temporal diffusion spectroscopy when only using oscillating diffusion gradients. Time-dependent diffusion (TDD) is emerging as a strong candidate for specific and non-invasive tumor characterization. Despite the lack of a general analytical solution for all diffusion times/frequencies, TDD can be probed in various regimes where systems simplify in order to extract relevant information about tissue microstructure. The fundamentals of TDD are first reviewed (a) in the short time regime, disentangling structural and diffusive tissue properties, and (b) near the tortuosity limit, assuming weakly heterogeneous media near infinitely long diffusion times. Focusing on cell bodies (as opposed to neuronal tracts), a simple but realistic model for intracellular diffusion can offer precious insight on diffusion inside biological systems, at all times. Based on this approach, the main three geometrical models implemented so far (IMPULSED, POMACE, VERDICT) are reviewed. Their suitability to quantify cell size, intra-and extracellular spaces (ICS and ECS) and diffusivities are assessed. The proper modeling of tissue membrane permeability-hardly a newcomer in the field, but lacking applications-and its impact on microstructural estimates are also considered. After discussing general issues with tissue modeling and microstructural parameter estimation (i.e., fitting), potential solutions are detailed. The in vivo applications of this new, non-invasive, specific approach in cancer are reviewed, ranging fromthe characterization of gliomas in rodent brains and observation of time-dependence in breast tissue lesions and prostate cancer, to the recent preclinical evaluation of new treatments efficacy. It is expected that clinical applications of TDD will strongly benefit the community in terms of non-invasive cancer screening.