The role of dendritic spines in water exchange measurements with diffusion MRI: Time-Dependent Single Diffusion Encoding MRI

Time-dependent diffusion MRI (dMRI) with single diffusion encoding (SDE) probes water dynamics in biological tissues, but signal interpretation depends on microstructure. While prior work focused on restricted/hindered diffusion and membrane permeation, diffusion-mediated exchange between dendritic shafts and spines in gray matter (GM) remains understudied. We hypothesize that impermeable spiny dendrites produce time-dependent SDE signals mimicking permeative exchange and investigate how spine density biases exchange time estimates. Using Monte Carlo simulations and narrow escape theory, we quantify spine-shaft exchange times (3-26 ms), matching cortical permeative exchange estimates. A modified two-compartment Karger model characterizes time-dependent SDE signals but yields biased exchange estimates, reflecting spine volume fraction rather than morphology. Unaccounted diffusion-mediated exchange introduces up to 80% bias in NEXI/SMEX model estimates. We propose an extended three-compartment Karger model incorporating both diffusion-mediated (spine-shaft) and permeative (intra-extracellular) exchange. However, this model cannot uniquely separate membrane permeability from spine volume effects. Our findings emphasize that dendritic spines should be considered in SDE-based exchange studies and caution against attributing exchange solely to permeability. Advanced methods are needed to disentangle these mechanisms in GM.