Project 1: Modeling Brain-State-Dependent Fluid Flow and Clearance in Mice and Humans

The overall goal for project 1 is to establish how neural activity drivesperiarterial CSF pumping and thereby glymphatic clearance of metabolic waste. We address that goal via fluid-dynamical modeling of flow at the microscale, flow at the macroscale, and brain-wide clearance – all in both mice and humans. We unify the microscale mechanisms and macroscale phenomena measured in Projects 2-4 and deliver predictive, quantitative, testable models. We postulate that neural circuit activity controls glymphatic function at the microscale via dynamics of the neurovascular unit, comprised of an arteriole, the perivascular space (PVS) surrounding it, and the surrounding neuropil.

Research Aims

Aim 1: Characterize periarterial CSF pumping in the neurovascular unit via fluid-dynamical simulations

Aim 2: Build a brain-wide fluid dynamical model of CSF flow in varying states in mice

Aim 3: Build a brain-wide solute clearance model in mice

Aim 4: Build models of CSF flow and solute transport in human brain

• Build models analogous to the models in Aim 1-3, but for humans instead of mice, informed by in vivo human studies (project 4)

Consistent with our originial program timeline, we expect to behin working on this Aim in year 3, in close collaboration with Project 4.

Publications 

A brain-wide solute transport model of the glymphatic system. K. Quirk, K. A. S. Boster, J. Tithof, and D. H.Kelley. To appear in J. R. Soc. Interface.

Restoration of cervical lymphatic vessel function in aging rescues cerebrospinal fluid drainage. T. Du, A. Raghunandan, H. Mestre, V. Plá, G. Liu, A. Ladrón-de-Guevara, E. Newbold, P. Tobin, D. Gahn-Martinez, S. Pattanayak, Q. Huang, W. Peng, M. Nedergaard, and D. H. Kelley. Nat. Aging 2024.

Gaps in the wall of a perivascular space act as valves to produce a directed flow of cerebrospinal fluid: A hoop-stress model. Y. Gan, J. H. Thomas, and D. H. Kelley. J. R. Soc. Interface. 2024.

Hydraulic resistance of three-dimensional pial perivascular spaces in the brain. K. A. S. Boster, J. Sun, J. K. Shang, D. H. Kelley, and J. H. Thomas. Fluids Barr. CNS. 2024.

Potentiating glymphatic drainage minimizes post-traumatic cerebral edema. R. Hussain, J. Tithof, W. Wang, A. Cheetham-West, W. Song, W. Peng, B. Sigurdsson, D. Kim, Q. Sun, S. Peng, V. Plá, D. H. Kelley, H. Hirase, J. A. Castorena-Gonzalez, P. Weikop, S. A. Goldman, M. J. Davis, and M. Nedergaard. Nature 2023.

Geometry-induced rectification of looped oscillatory flows. R. Ibanez, A. Raghunandan, and D. H. Kelley. Phys. Rev. Fluids 2023.

Image Analysis Techniques for In Vivo Quantification of Cerebrospinal Fluid Flow. D. Kim, Y. Gan, M. Nedergaard, D. H. Kelley, and J. Tithof. Exp. Fluids 2023.

Perivascular pumping of cerebrospinal fluid in the brain with a valve mechanism. Y. Gan, S. Holstein-Rønsbo, M. Nedergaard, K. A. S. Boster, J. H. Thomas, and D. H. Kelley. J. R. Soc. Interface 2023.

Sizes and shapes of perivascular spaces surrounding murine pial arteries. N. Raicevic, J. M. Forer, A. Ladrón-de-Guevara, T. Du, M. Nedergaard, D. H. Kelley and K. Boster. Fluids Barr. CNS. 2023.

Glymphatic influx and clearance are accelerated by neurovascular coupling. S. Holstein-Rønsbo, Y. Gan, M. K. Rasmussen, B. Sigurdsson, F. R. M. Beinlich, L. Hablitz, M. Giannetto, L. Rose, D. H. Kelley, and M. Nedergaard. Nat. Neurosci. 2023.

Artificial intelligence velocimetry reveals in vivo flow rates, pressure gradients, and shear stresses in murine perivascular flows. K. A. S. Boster, S. Cai, A. Ladrón-de-Guevara, J. Sun, X. Zheng, T. Du, J. H. Thomas, M. Nedergaard, G. E. Karniadakis, and D. H. Kelley. Proc. Nat. Acad. Sci. 2023.

Cerebrospinal fluid flow. D. H. Kelley and J. H. Thomas. Annu. Rev. Fluid Mech. 2023.