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Abstract BackgroundPerivascular spaces (PVSs) carry cerebrospinal fluid (CSF) around the brain, facilitating healthy waste clearance. Measuring those flows in vivo is difficult, and often impossible, because PVSs are small, so accurate modeling is essential for understanding brain clearance. The most important parameter for modeling flow in a PVS is its hydraulic resistance, defined as the ratio of pressure drop to volume flow rate, which depends on its size and shape. In particular, the local resistance per unit length varies along a PVS and depends on variations in the local cross section. MethodsUsing segmented, three-dimensional images of pial PVSs in mice, we performed fluid dynamical simulations to calculate the resistance per unit length. We applied extended lubrication theory to elucidate the difference between the calculated resistance and the expected resistance assuming a uniform flow. We tested four different approximation methods, and a novel correction factor to determine how to accurately estimate resistance per unit length with low computational cost. To assess the impact of assuming unidirectional flow, we also considered a circular duct whose cross-sectional area varied sinusoidally along its length. ResultsWe found that modeling a PVS as a series of short ducts with uniform flow, and numerically solving for the flow in each, yields good resistance estimates at low cost. If the second derivative of area with respect to axial location is less than 2, error is typically less than 15%, and can be reduced further with our correction factor. To make estimates with even lower cost, we found that instead of solving for the resistance numerically, the well-known resistance of a circular duct could be scaled by a shape factor. As long as the aspect ratio of the cross section was less than 0.7, the additional error was less than 10%. ConclusionsNeglecting off-axis velocity components underestimates the average resistance, but the error can be reduced with a simple correction factor. These results could increase the accuracy of future models of brain-wide and local CSF flow, enabling better prediction of clearance, for example, as it varies with age, brain state, and pathological conditions.