Impact of blood-brain barrier permeabilisation with focused ultrasound: a quantitative MRI approach

On Thursday, November 21st 2024, Sébastien RIGOLLET will defend his thesis "Impact of blood-brain barrier permeabilisation with focused ultrasound: a quantitative MRI approach".

This thesis has been directed by Emmanuel BARBIER of the "Functional Neuroimaging and Brain Perfusion" team of the GIN and Chantal PICHON.

Jury members

- Cyril Lafon, INSERM délégation Auvergne-Rhône-Alpes, Rapporteur
- Lori Bridal, CNRS délégation Paris Centre, Rapporteur
- Marlène Wiart, CNRS Délégation Rhône Auvergne, Examinateure
- Clemens Bos, University Medical Center Utrech, Examinateur
- Mireille Albrieux, Université Grenoble Alpes, Examinateure
- Dumont Erik, Imagine Guided Therapy, Invité
- Chantal Pichon, Université d’Orléans, Co-Directrice de thèse
- Emmanuel Barbier, GIN Université Grenoble-Alpes, Directeur de thèse

Abstract

The blood-brain barrier (BBB) hinders efficient delivery of therapeutic compounds to the central nervous system (CNS) due to a structure gathering endothelial cells maintained by tight junctions, astrocytes and pericytes. The prevalence of neurological diseases is constantly increasing. The effectiveness of therapeutic agents that are already on the market or have been validated in pre-clinical trials is largely limited because the BBB prevents them from working. Recently, the use of focused ultrasound (FUS) coupled with a systemic vascular injection of gas microbubbles and guided by magnetic resonance imaging (MRI) has demonstrated excellent efficacy in reversibly permeabilising the BBB and thus locally increasing drug deposits. The mechanical action exerted by the gas microbubbles on the endothelial walls triggers a cascade of secondary effects that remain little studied to date, particularly at the level of cerebral microvascularisation.

The aim of this thesis was to characterise the impact of FUS on cerebral microvascularisation using innovative quantitative MRI methods and at microscopic level with histological analyses of neuroinflammation markers. First, we characterised changes in cerebral perfusion and neuroinflammation after BBB permeabilisation and then changes during repeated BBB permeabilisation longitudinally using an MRI fingerprint approach. We then applied different FUS treatment patterns, firstly in an orthotopic model of glioblastoma to deliver chemotherapy in combination with radiotherapy, and in a transgenic model of Fragile X syndrome to deliver a gene therapy. From the characterisation and understanding of the side effects of BBB permeabilisation by FUS to the application of this innovative method to deliver therapies, this work provides a better understanding of the use of FUS in the brain and enables us to rethink treatment parameters to ensure the best possible transfer to the clinic.

Keywords: Focused ultrasound, Secondary bioeffects, Quantitative MRI, Glioblastoma