Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates

Abstract An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gr...

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Autores principales:	Antonios N. Pouliopoulos, Nancy Kwon, Greg Jensen, Anna Meaney, Yusuke Niimi, Mark T. Burgess, Robin Ji, Alicia J. McLuckie, Fabian A. Munoz, Hermes A. S. Kamimura, Andrew F. Teich, Vincent P. Ferrera, Elisa E. Konofagou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a8810ff79a67460bb0d1b9296c6a333f
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spelling	oai:doaj.org-article:a8810ff79a67460bb0d1b9296c6a333f2021-12-02T17:55:09ZSafety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates10.1038/s41598-021-94188-32045-2322https://doaj.org/article/a8810ff79a67460bb0d1b9296c6a333f2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94188-3https://doaj.org/toc/2045-2322Abstract An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.Antonios N. PouliopoulosNancy KwonGreg JensenAnna MeaneyYusuke NiimiMark T. BurgessRobin JiAlicia J. McLuckieFabian A. MunozHermes A. S. KamimuraAndrew F. TeichVincent P. FerreraElisa E. KonofagouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Antonios N. Pouliopoulos Nancy Kwon Greg Jensen Anna Meaney Yusuke Niimi Mark T. Burgess Robin Ji Alicia J. McLuckie Fabian A. Munoz Hermes A. S. Kamimura Andrew F. Teich Vincent P. Ferrera Elisa E. Konofagou Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
description	Abstract An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.
format	article
author	Antonios N. Pouliopoulos Nancy Kwon Greg Jensen Anna Meaney Yusuke Niimi Mark T. Burgess Robin Ji Alicia J. McLuckie Fabian A. Munoz Hermes A. S. Kamimura Andrew F. Teich Vincent P. Ferrera Elisa E. Konofagou
author_facet	Antonios N. Pouliopoulos Nancy Kwon Greg Jensen Anna Meaney Yusuke Niimi Mark T. Burgess Robin Ji Alicia J. McLuckie Fabian A. Munoz Hermes A. S. Kamimura Andrew F. Teich Vincent P. Ferrera Elisa E. Konofagou
author_sort	Antonios N. Pouliopoulos
title	Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
title_short	Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
title_full	Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
title_fullStr	Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
title_full_unstemmed	Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
title_sort	safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a8810ff79a67460bb0d1b9296c6a333f
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Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates

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