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advection, Alzheimer’s disease, amyloid, biophysics, blood brain barrier, bulk flow, cerebrospinal fluid, circulation, extracellular, hydraulic, intracranial pressure, perivascular pumping, permeability, pia mater, pulsation, subarachnoid space, Virchow-Robin space, waste.


Objective. To explore the biophysics of interstitial tissue fluid flow in the brain, based upon the anatomy and mechanics of the perivascular spaces, in order to better understand how glymphatic flow happens. Methods. The dynamics of fluid flow at cardiac frequencies are investigated in rapidly computable, branched, geometric models of brain tissue at multiple scales. The models are supplied by intermingled trees of penetrating arteries and veins. They include pulsatile changes in intracranial pressure and intravascular pressure, elastic expansion of brain tissue, and nonlinear changes in resistance to flow of cerebrospinal fluid along the axis of the Virchow-Robin space. Resulting changes in periarterial and perivenous pressures and the resulting bulk flow of interstitial fluid from arteriolar to venular perivascular spaces are calculated on a laptop computer. Results. Under typical physiological conditions a time averaged positive pressure of ~ 0.5 mmHg develops between the smaller, distal periarteriolar and perivenous branches. Based on tissue geometry and hydraulic resistance, the resulting flow is sufficient to refresh the interstitial fluid once every 1 to 10 hours. The effect is degraded by increasing radial widths of the perivascular spaces. The calculated average glymphatic flow through the whole brain is similar to the measured production of new cerebrospinal fluid by the arachnoid villi. Conclusions. When the branching structure of perivascular trees is properly considered, their classical anatomy has surprising emergent properties. Biologically meaningful amounts of advective flow can happen between smaller, distal branches of periarteriolar and perivenous spaces.