Neuronal Activity-Dependent Electroosmosis and Its Potential Role in Interstitial Fluid Flow in the Glymphatic System

Abstract

The mechanisms driving interstitial fluid flow through brain parenchyma remain unresolved, limiting our understanding of how fluid transport contributes to glymphatic waste clearance and broader aspects of brain metabolism and neuronal activity. Existing theories based on diffusion or pressure gradients fail to explain sustained, directional flow through the tortuous extracellular space (ECS), particularly under normal physiologic conditions. Here we propose that electroosmosis, fluid motion driven by endogenous electric fields acting on charged brain tissue, provides a biophysically consistent mechanism for intraparenchymal interstitial fluid transport while generating pressure distributions favorable for periarterial influx and perivenous efflux. Using computational modeling informed by anatomical reconstructions of ECS microstructure and local field potential (LFP) recordings, we show that electroosmotic flow generates physiologically realistic velocities and reproduces brain state dependent differences in glymphatic transport, including the enhanced glymphatic flow observed during sleep compared to wakefulness. A physics-informed reduced-order model (ROM) further demonstrates that these microstructure-resolved results upscale consistently to tissue-level transport. Moreover, electroosmotic flow can induce directional pressure gradients across perivascular interfaces, facilitating both influx and efflux. This mechanism provides a unifying framework linking neuronal activity, parenchymal flow, and compartmental pressure regulation. In contrast, pressure gradients substantially larger than physiological estimates generated much smaller velocities and failed to account for the observed transport rates. These findings address a major gap in glymphatic physiology and suggest that modulation of electric field properties, via endogenous activity or external neuromodulation, could serve as a therapeutic strategy to enhance solute clearance in neurological disorders. Significance StatementA major challenge in brain physiology is the lack of a unifying physical model that explains how fluid moves through the narrow and tortuous extracellular space; a process essential for nutrient distribution and waste clearance. Existing frameworks cannot account for sustained, directional transport under normal physiological conditions. We show that electroosmosis (fluid motion generated when endogenous neuronal electric fields act on charged cellular surfaces) provides a biophysically consistent mechanism for this transport. Using realistic extracellular microstructures and a validated tissue scale reduced order model, our model reproduces experimentally observed brain state dependent transport. Establishing electroosmosis as a possible contributor to interstitial fluid movement offers a new conceptual basis for linking neuronal activity to fluid circulation and for guiding strategies to enhance brain clearance.