A number of new theories have emerged including the glymphatic system , the intramural periarterial drainage (IPAD) theory , and the Bulat–Klarica–Oreskovic hypothesis, along with critical evaluations . Over the last decade, there has been a significant renewed interest in the waterscape of the brain that is, the physiological mechanisms governing cerebrospinal fluid (CSF) and interstitial fluid (ISF) flow in (and around) the brain parenchyma. A glymphatic velocity field may increase transport if a large-scale directional structure is included in the glymphatic circulation. ConclusionĮven when uncertainties are taken into account, we find that diffusion alone is not sufficient to explain transport of tracer deep into the white matter as seen in experimental data. In a model including drainage directly from the brain parenchyma, time to peak occured after 6–8 h for the gray matter. However, the expected time to peak was reduced to 11 h when an additional directionality was prescribed for the glymphatic circulation. Models of the glymphatic system were similar qualitatively to the models of pure diffusion with respect to expected time to peak but displayed less variability. In models of pure diffusion, the expected amount of tracer in the gray matter reached peak value after 15 h, while the white matter did not reach peak within 24 h with high likelihood. Our results were compared with experimental MRI results of tracer enhancement. Several models were tested to assess the uncertainty both in type of diffusion and velocity fields and also the importance of their magnitude. Using the convection–diffusion–reaction equation, we simulated tracer distribution in the brain parenchyma after intrathecal injection. In this work, we rigorously quantified the variability of tracer distribution in the brain resulting from uncertainty in diffusion and convection model parameters. Accurate modeling of tracer distributions in the brain relies on parameters that are partially unknown and with literature values varying by several orders of magnitude. Influx and clearance of substances in the brain parenchyma occur by a combination of diffusion and convection, but the relative importance of these mechanisms is unclear.
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