Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection

  1. Aditya Raghunandan
  2. Antonio Ladron-de-Guevara
  3. Jeffrey Tithof
  4. Humberto Mestre
  5. Ting Du
  6. Maiken Nedergaard
  7. John H Thomas
  8. Douglas H Kelley  Is a corresponding author
  1. University of Rochester, United States
  2. University of Rochester Medical Center, United States
  3. University of Minnesota, United States

Abstract

Cerebrospinal fluid (CSF) flowing through periarterial spaces is integral to the brain's mechanism for clearing metabolic waste products. Experiments that track tracer particles injected into the cisterna magna of mouse brains have shown evidence of pulsatile CSF flow in perivascular spaces surrounding pial arteries, with a bulk flow in the same direction as blood flow. However, the driving mechanism remains elusive. Several studies have suggested that the bulk flow might be an artifact, driven by the injection itself. Here, we address this hypothesis with new in vivo experiments where tracer particles are injected into the cisterna magna using a dual-syringe system, with simultaneous injection and withdrawal of equal amounts of fluid. This method produces no net increase in CSF volume and no significant increase in intracranial pressure. Yet, particle-tracking reveals flows that are consistent in all respects with the flows observed in earlier experiments with single-syringe injection.

Data availability

All data generated or analyzed for this study are included in the manuscript. Source data files have been provided for Figures 4a, 4d, 4e, and 5i.The particle-tracking Matlab code used in this study is available in the public domain GitLab repository found here: https://gitlab-public.circ.rochester.edu/araghuna/bulk-flow-is-not-an-artifact_raghunandan_et_al_2021.git

Article and author information

Author details

  1. Aditya Raghunandan

    Mechanical Engineering, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1938-0184
  2. Antonio Ladron-de-Guevara

    Biomedical Engineering, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jeffrey Tithof

    Mechanical Engineering, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2083-0901
  4. Humberto Mestre

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5876-5397
  5. Ting Du

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Maiken Nedergaard

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. John H Thomas

    Department of Mechanical Engineering, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Douglas H Kelley

    Mechanical Engineering, University of Rochester, Rochester, United States
    For correspondence
    d.h.kelley@rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9658-2954

Funding

National Institutes of Health (RF1AG057575)

  • Maiken Nedergaard
  • John H Thomas
  • Douglas H Kelley

Army Research Office (MURI W911NF1910280)

  • Antonio Ladron-de-Guevara
  • Humberto Mestre
  • Maiken Nedergaard
  • John H Thomas
  • Douglas H Kelley

Burroughs Wellcome Fund (Career Award at the Scientific Interface)

  • Jeffrey Tithof

The funding agencies did not influence study design, data collection, and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were approved and conducted in accordance with the relevant guidelines and regulations stipulated by theUniversity Committee on Animal Resources of the University of Rochester Medical Center (Protocol No. 2011-023), certifiedby Association for Assessment and Accreditation of Laboratory Animal Care.

Reviewing Editor

  1. Claire Wyart, Institut du Cerveau et la Moelle épinière, Hôpital Pitié-Salpêtrière, Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, France

Publication history

  1. Received: December 20, 2020
  2. Accepted: March 8, 2021
  3. Accepted Manuscript published: March 9, 2021 (version 1)
  4. Version of Record published: March 19, 2021 (version 2)

Copyright

© 2021, Raghunandan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Aditya Raghunandan
  2. Antonio Ladron-de-Guevara
  3. Jeffrey Tithof
  4. Humberto Mestre
  5. Ting Du
  6. Maiken Nedergaard
  7. John H Thomas
  8. Douglas H Kelley
(2021)
Bulk flow of cerebrospinal fluid observed in periarterial spaces is not an artifact of injection
eLife 10:e65958.
https://doi.org/10.7554/eLife.65958

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