Williamson Nathan H, Ravin Rea, Cai Teddy X, Rey Julian A, Basser Peter J
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Military Traumatic Brain Injury Initiative (MTBI), Bethesda, MD 20814, USA.
bioRxiv. 2025 Jul 2:2025.05.27.655493. doi: 10.1101/2025.05.27.655493.
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 -ATPase pump-leak 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 -ATPase 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's 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.
多孔材料，如生物组织，通常具有异质微观结构，其中吸入的流体在短时间尺度上经历不同的环境，但在长时间尺度上可以在不同环境之间交换。诸如扩散交换光谱法（DEXSY）之类的核磁共振（NMR）方法可以在稳态和平衡条件下测量水中的这种交换；然而，当涉及两个以上的交换环境时，建模会变得更加复杂。这种复杂性在中枢神经系统（CNS）中尤为重要，在那里细胞水平的水扩散和交换在体内平衡中起着关键作用。虽然DEXSY可以测量这些过程，但它们可能不能充分地建模为细胞内和细胞外空间（ICS和ECS）之间的双位点交换。在这里，我们研究了从使用三点交换模型（3XM）进行数值模拟的DEXSY数据估计的表观交换速率常数（AXR）的行为。3XM基于灰质微观结构特征，纳入了ECS和ICS之间的跨膜交换以及ICS内不同环境之间的几何交换，在ICS内，由于神经元、神经胶质细胞和ECS的复杂结构，水的流动性有所不同。受细胞体积维持的 -ATPase泵-漏模型的启发，3XM考虑了渗透溶质、离子和电压对ECS和ICS体积分数的影响。该模型预测，在预期的 -ATPase抑制引起的膜去极化水平之后，AXR会显著降低，表观扩散系数（ADC）的降低幅度较小。与先前的实验一致，添加与电压无关的膜不可渗透的ECS渗透溶质可逆转这些变化。虽然每个途径的交换速率常数仅遵循一级动力学，但AXR对这些途径的敏感性取决于ECS体积分数。当存在ECS时，跨膜交换占主导地位，但当泵抑制后细胞肿胀时，几何交换成为主要途径。
