Passive water exchange between multiple sites can explain why apparent exchange rate constants depend on ionic and osmotic conditions in gray matter.

Porous materials, such as biological tissue, often have heterogeneous microstructures where imbibed fluid experiences distinct environments on short timescales, but can exchange among different environments over long timescales. Nuclear magnetic resonance (NMR) methods such as diffusion exchange spectroscopy (DEXSY) can measure this exchange in water under steady-state and equilibrium conditions; however, modeling becomes more complex when more than two exchanging environments are involved. This complexity is particularly relevant in the central nervous system (CNS), where water diffusion and exchange at the cellular level play critical roles in homeostasis. While DEXSY can measure these processes, they may not be adequately modeled as two-site exchange between intracellular and extracellular spaces (ICS and ECS). Here we study the behavior of apparent exchange rate constants (AXR) estimated from DEXSY data numerically simulated using a three-site exchange model (3XM). The 3XM is based on gray matter microstructural characteristics, incorporating both transmembrane exchange between ECS and ICS and geometric exchange between environments within ICS where water mobility differs due to the complex architecture of neurons, glial cells, and the ECS. Inspired by the Na