title: Magnetic resonance-guided motorized transcranial ultrasound system for blood-brain barrier permeabilization along arbitrary trajectories in rodents.
abstract: BACKGROUND
  Focused ultrasound combined with microbubble injection is capable of locally and transiently enhancing the permeability of the blood-brain barrier (BBB). Magnetic resonance imaging (MRI) guidance enables to plan, monitor, and characterize the BBB disruption. Being able to precisely and remotely control the permeabilization location is of great interest to perform reproducible drug delivery protocols.
  
  
  METHODS
  In this study, we developed an MR-guided motorized focused ultrasound (FUS) system allowing the transducer displacement within preclinical MRI scanners, coupled with real-time transfer and reconstruction of MRI images, to help ultrasound guidance. Capabilities of this new device to deliver large molecules to the brain on either single locations or along arbitrary trajectories were characterized in vivo on healthy rats and mice using 1.5 MHz ultrasound sonications combined with microbubble injection. The efficacy of BBB permeabilization was assessed by injecting a gadolinium-based MR contrast agent that does not cross the intact BBB.
  
  
  RESULTS
  The compact motorized FUS system developed in this work fits into the 9-cm inner diameter of the gradient insert installed on our 7-T preclinical MRI scanners. MR images acquired after contrast agent injection confirmed that this device can be used to enhance BBB permeability along remotely controlled spatial trajectories of the FUS beam in both rats and mice. The two-axis motor stage enables reaching any region of interest in the rodent brain. The positioning error when targeting the same anatomical location on different animals was estimated to be smaller than 0.5 mm. Finally, this device was demonstrated to be useful for testing BBB opening at various acoustic pressures (0.2, 0.4, 0.7, and 0.9 MPa) in the same animal and during one single ultrasound session.
  
  
  CONCLUSIONS
  Our system offers the unique possibility to move the transducer within a high magnetic field preclinical MRI scanner, thus enabling the delivery of large molecules to virtually any rodent brain area in a non-invasive manner. It results in time-saving and reproducibility and could be used to either deliver drugs over large parts of the brain or test different acoustic conditions on the same animal during the same session, therefore reducing physiological variability.
authors.affiliation: UNIRS, Neurospin, I2BM, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique et aux Energies Alternatives, Bâtiment 145, 91191 Gif sur Yvette, France ; Image Guided Therapy, 4 allée du doyen Brus, 33600 Pessac, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Magnin
authors.affiliation: Image Guided Therapy, 4 allée du doyen Brus, 33600 Pessac, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Rabusseau
authors.affiliation: Image Guided Therapy, 4 allée du doyen Brus, 33600 Pessac, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Salabartan
authors.affiliation: UNIRS, Neurospin, I2BM, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique et aux Energies Alternatives, Bâtiment 145, 91191 Gif sur Yvette, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Mériaux
authors.affiliation: CNRS UMR 7587, INSERM U979, ESPCI ParisTech, Institut Langevin Ondes et Images, 1 rue Jussieu, 75005 Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Aubry
authors.affiliation: UNIRS, Neurospin, I2BM, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique et aux Energies Alternatives, Bâtiment 145, 91191 Gif sur Yvette, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Le Bihan
authors.affiliation: Image Guided Therapy, 4 allée du doyen Brus, 33600 Pessac, France.
authors.forename: Erik
authors.initials: E
authors.lastname: Dumont
authors.affiliation: UNIRS, Neurospin, I2BM, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique et aux Energies Alternatives, Bâtiment 145, 91191 Gif sur Yvette, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Larrat
keywords: Blood-brain barrier permeabilization; Drug delivery to rodent brains; Focused ultrasound; High-field magnetic resonance imaging