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Increasing BBB Permeability via Focused Ultrasound: Current Methods in Preclinical Research

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Blood-Brain Barrier

Part of the book series: Neuromethods ((NM,volume 142))

Abstract

The tightly regulated permeance of the blood-brain barrier (BBB) greatly limits the range of therapeutic treatment options for central nervous system (CNS) diseases. The use of focused ultrasound (FUS), in conjunction with circulating microbubbles, is a unique approach whereby the transcranial application of acoustic energy, focused within targeted brain areas, can be used to induce a noninvasive, transient, and targeted increase in BBB permeability. This can provide an avenue for the delivery of therapeutic agents from the systemic circulation into the brain. While this approach continues to show great promise and has entered clinical testing, there remains a need for preclinical research to investigate the long-term effects of single and repeated FUS treatment on cerebrovascular health and neurological function, as well the pharmacokinetics of specific drugs following FUS. Additionally, there is a need for improved monitoring strategies that can precisely predict resulting bio-effects. This will allow the continued development of control algorithms that can further increase the safety profile of FUS. Here we will describe two approaches to study FUS-mediated increases in BBB permeability in rodent models: MRI-guided FUS and in vivo two-photon fluorescence microscopy FUS experiments. The goal of this chapter is to outline each procedure, present options for experimental design, and highlight important considerations for the collection and interpretation of data.

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Acknowledgements

We gratefully acknowledge our funding sources: Canadian Institutes of Health Research (MOP 119312) and the National Institutes of Health (R01 EB003268). The authors would also like to thank Marc Santos for his MATLAB script used to analyze gadolinium contrast enhancement, Shawna Rideout-Gros for her expertise with the cranial windows, and Marcelline Ramcharan for her administrative assistance.

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Author notes

  1. Dallan McMahon and Charissa Poon contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Dallan McMahon & Kullervo Hynynen

  2. Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada

    Dallan McMahon, Charissa Poon & Kullervo Hynynen

  3. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

    Charissa Poon & Kullervo Hynynen

Authors
  1. Dallan McMahon
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  2. Charissa Poon
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  3. Kullervo Hynynen
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Corresponding authors

Correspondence to Dallan McMahon or Charissa Poon .

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Editors and Affiliations

  1. Department of Psychiatry & Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Tatiana Barichello

Supplementary Materials

Supplementary Materials

Equipment:

  • Surgical scissors*

  • Surgical forceps*

  • Fine surgical forceps*

  • Cotton swabs*

  • Fibreless swabs*

  • Gelfoam

  • Stereotax for rodents

    • Bite bar

    • Ear bars

  • Warming pad

  • Dental drill

  • Micro drill burr* (0.5 mm, Fine Science Tools)

  • Circular cover glass (5, 8, or 12 mm diameter, #1 thickness, Warner Instruments)

  • Drapes*

  • Kimpwipes*

  • Small glass beaker or Petri dish*

  • Spatula*

  • Dissection microscope

  • 1 mL syringe

  • 5 mL syringe

* Autoclave (or use new) if doing sterile surgeries for a chronic cranial window.

Chemicals:

  • Depilatory cream (sensitive)

  • Baby shampoo

  • Warm water

  • Agarose

Drugs:

  • Isoflurane

  • Ketoprofen (5 mg/kg)

  • Carprofen (5 mg/kg)

  • Dexamethasone (0.2 mg/kg)

  • 1% lidocaine

  • Lactated Ringer’s solution, or saline

  • Eye lubrication

  • Topical antibiotic cream

  • Prophylactic antibiotics

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McMahon, D., Poon, C., Hynynen, K. (2019). Increasing BBB Permeability via Focused Ultrasound: Current Methods in Preclinical Research. In: Barichello, T. (eds) Blood-Brain Barrier. Neuromethods, vol 142. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8946-1_16

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  • DOI: https://doi.org/10.1007/978-1-4939-8946-1_16

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8945-4

  • Online ISBN: 978-1-4939-8946-1

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