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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\n                  <jats:sup>+<\/jats:sup>\n                  \/K\n                  <jats:sup>+<\/jats:sup>\n                  \u2013ATPase pump\u2013leak model of cell volume maintenance, the 3XM accounts for effects of osmolytes, ions, and voltage on ECS and ICS volume fraction. The model predicts a significant reduction in AXR and a smaller decrease in apparent diffusion coefficients (ADC) following the level of membrane depolarization expected from Na\n                  <jats:sup>+<\/jats:sup>\n                  \/K\n                  <jats:sup>+<\/jats:sup>\n                  \u2013ATPase inhibition. These changes were reversed by the addition of membrane-impermeable ECS osmolytes, independent of voltage, in agreement with previous experiments. While the exchange rate constants for each pathway simply follow first-order kinetics, the AXR\u2019s sensitivity to these pathways depends on the ECS volume fraction. When ECS is present, transmembrane exchange dominates, but when cells swell following pump inhibition, geometric exchange becomes the dominant pathway.\n                <\/jats:p>","DOI":"10.1101\/2025.05.27.655493","type":"posted-content","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T05:30:17Z","timestamp":1748410217000},"source":"Crossref","is-referenced-by-count":3,"title":["Passive water exchange between multiple sites can explain why apparent exchange rate constants depend on ionic and osmotic conditions in gray matter"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0221-9121","authenticated-orcid":false,"given":"Nathan H.","family":"Williamson","sequence":"first","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Military Traumatic Brain Injury Initiative (MTBI2), Bethesda, MD 20814, USA"},{"name":"Uniformed Services University of the Health Sciences (USU), Bethesda, Maryland 20814, USA"},{"name":"The Henry M. 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