Magnetic resonance-guided motorized transcranial ultrasound system for blood-brain barrier permeabilization along arbitrary trajectories in rodents

Journal of Therapeutic Ultrasound

Benoit Larrat²  Erik Dumont³  Denis Le Bihan²  Jean-François Aubry¹  Sébastien Mériaux²  Frédéric Salabartan³  Fabien Rabusseau³  Rémi Magnin³ 

[1] CNRS UMR 7587, INSERM U979, ESPCI ParisTech, Institut Langevin Ondes et Images, 1 rue Jussieu, Paris, 75005, France;UNIRS, Neurospin, I2BM, Direction des Sciences du Vivant, Commissariat à l’Energie Atomique et aux Energies Alternatives, Bâtiment 145, Gif sur Yvette, 91191, France;Image Guided Therapy, 4 allée du doyen Brus, Pessac, 33600, France

关键词: Drug delivery to rodent brains;    High-field magnetic resonance imaging;    Focused ultrasound;    Blood-brain barrier permeabilization;   

Others  :  1235075
DOI  :  10.1186/s40349-015-0044-5

 received in 2015-09-02, accepted in 2015-12-18,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Magnin et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 5.

Fig. 6.

Fig. 7.

【 参考文献 】

• [1]Tyshlek D, Aubry J-F, Ter Haar G, Hananel A, Foley J, Eames M et al.. Focused ultrasound development and clinical adoption: 2013 update on the growth of the field. J Ther Ultrasound. 2014; 2:2. BioMed Central Full Text
• [2]Blana A, Murat FJ, Walter B, Thuroff S, Wieland WF, Chaussy C et al.. First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer. Eur Urol. 2008; 53:1194-203.
• [3]Uchida T, Shoji S, Nakano M, Hongo S, Nitta M, Murota A et al.. Transrectal high-intensity focused ultrasound for the treatment of localized prostate cancer: eight-year experience. Int J Urol. 2009; 16:881-6.
• [4]Wu F, Wang ZB, Chen WZ, Wang W, Gui Y, Zhang M et al.. Extracorporeal high intensity focused ultrasound ablation in the treatment of 1038 patients with solid carcinomas in China: an overview. Ultrason Sonochem. 2004; 11:149-54.
• [5]Aubry J, Pauly KB, Moonen C, Ter Haar G, Ries M, Salomir R et al.. The road to clinical use of high-intensity focused ultrasound for liver cancer: technical and clinical consensus. J Ther Ultrasound. 2013; 1:13. BioMed Central Full Text
• [6]Fennessy FM, Tempany CM. A review of magnetic resonance imaging-guided focused ultrasound surgery of uterine fibroids. Top Magn Reson Imaging. 2006; 17:173-9.
• [7]Voogt M, Trillaud H, Kim Y, Mali W-T-M, Barkhausen J, Bartels LW et al.. Volumetric feedback ablation of uterine fibroids using magnetic resonance-guided high intensity focused ultrasound therapy. Eur Radiol. 2012; 22:411-7.
• [8]Liberman B, Gianfelice D, Inbar Y, Beck A, Rabin T, Shabshin N et al.. Pain palliation in patients with bone metastases using MR-guided focused ultrasound surgery: a multicenter study. Ann Surg Oncol. 2009; 16:140-6.
• [9]Lam MK, Huisman M, Nijenhuis RJ, van den Bosch MA, Viergever MA, Moonen C et al.. Quality of MR thermometry during palliative MR-guided high-intensity focused ultrasound (MR-HIFU) treatment of bone metastases. J Ther ultrasound. 2015; 3:1-15. BioMed Central Full Text
• [10]Martin E, Jeanmonod D, Morel A, Zadicario E, Werner B. High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann Neurol. 2009;66(6):858-61. doi:. 10. 1002/ana.21801 webcite
• [11]Elias WJ, Huss D, Voss T, Loomba J, Khaled M, Zadicario E et al.. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2013; 369:640-8.
• [12]Hynynen K, Mcdannold N. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology. 2001; 220:640-6.
• [13]O’Reilly MA, Hynynen K. Ultrasound enhanced drug delivery to the brain and central nervous system. Int J Hyperthermia. 2012; 28:386-96.
• [14]Couture O, Foley J, Kassell NF, Larrat B, Aubry J. Review of ultrasound mediated drug delivery for cancer treatment: updates from pre-clinical studies. Transl Cancer Res. 2014; 3:494-511.
• [15]Treat LH, McDannold N, Vykhodtseva N, Zhang Y, Tam K, Hynynen K. Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer. 2007; 121:901-7.
• [16]Fan C-H, Ting C-Y, Liu H-L, Huang C-Y, Hsieh H-Y, Yen T-C et al.. Antiangiogenic-targeting drug-loaded microbubbles combined with focused ultrasound for glioma treatment. Biomaterials. 2013; 34:2142-55.
• [17]Jordão JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R, McLaurin J et al.. Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer’s disease. PLoS One. 2010; 5:e10549.
• [18]Raymond SB, Treat LH, Dewey JD, McDannold NJ, Hynynen K, Bacskai BJ. Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer’s disease mouse models. PLoS One. 2008; 3:e2175.
• [19]Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem Biophys Res Commun. 2006; 340:1085-90.
• [20]Aryal M, Arvanitis CD, Alexander PM, McDannold N. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system. Adv Drug Deliv Rev. 2014; 0:94-109.
• [21]Jordão JF, Thévenot E, Markham-Coultes K, Scarcelli T, Weng Y-Q, Xhima K et al.. Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol. 2013; 248C:16-29.
• [22]Leinenga G, Götz J. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’ s disease mouse model. Sci Trans Med. 2015; 7:278.
• [23]Vlachos F, Tung Y-S, Konofagou E. Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI. Magn Reson Med. 2011; 66:821-30.
• [24]Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vykhodtseva N. Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage. 2005; 24:12-20.
• [25]O’Reilly MA, Huang Y, Hynynen K, Reilly MAO. The impact of standing wave effects on transcranial focused ultrasound disruption of the blood-brain barrier in a rat model. Phys Med Biol. 2010; 55:5251-67.
• [26]O’Reilly MA, Waspe AC, Ganguly M, Hynynen K. Focused-ultrasound disruption of the blood-brain barrier using closely-timed short pulses: influence of sonication parameters and injection rate. Ultrasound Med Biol. 2011; 37:587-94.
• [27]Samiotaki G, Vlachos F, Tung Y-S, Konofagou EE. A quantitative pressure and microbubble-size dependence study of focused ultrasound-induced blood-brain barrier opening reversibility in vivo using MRI. Magn Reson Med. 2012; 67:769-77.
• [28]McDannold N, Vykhodtseva N, Hynynen K. Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med Biol. 2008; 34:930-7.
• [29]McDannold N, Zhang Y, Vykhodtseva N. Blood-brain barrier disruption and vascular damage induced by ultrasound bursts combined with microbubbles can be influenced by choice of anesthesia protocol. Ultrasound Med Biol. 2011; 37:1259-70.
• [30]Marty B, Larrat B, Van Landeghem M, Robic C, Robert P, Port M et al.. Dynamic study of blood-brain barrier closure after its disruption using ultrasound: a quantitative analysis. J Cereb Blood Flow Metab. 2012; 32:1948-58.
• [31]Larrat B, Pernot M, Aubry J-F, Dervishi E, Sinkus R, Seilhean D et al.. MR-guided transcranial brain HIFU in small animal models. Phys Med Biol. 2010; 55:365-88.
• [32]Mcdannold N, Maier SE. Magnetic resonance acoustic radiation force imaging. Med Phys. 2007; 35:3748-58.
• [33]Vlachos F, Tung Y-S, Konofagou EE. Permeability assessment of the focused ultrasound-induced blood-brain barrier opening using dynamic contrast-enhanced MRI. Phys Med Biol. 2010; 55:5451-66.
• [34]Chopra R, Curiel L, Staruch R, Morrison L, Hynynen K. An MRI-compatible system for focused ultrasound experiments in small animal models. Med Phys. 2009; 36:1867-74.
• [35]Jensen JA, Lyngby D. Field : a program for simulating ultrasound systems. Med Biol Eng Comput. 1996; 34:351-3.
• [36]Bæk D, Jensen JA, Willatzen M. Modeling transducer impulse responses for predicting calibrated pressure pulses with the ultrasound simulation program Field II. J Acoust Soc Am. 2010; 127:2825-35.
• [37]Younan Y, Deffieux T, Larrat B, Fink M, Tanter M, Aubry J-F. Influence of the pressure field distribution in transcranial ultrasonic neurostimulation. Med Phys. 2013; 40:082902.
• [38]Tufail Y, Matyushov A, Baldwin N, Tauchmann M-L, Georges J, Yoshihiro A et al.. Transcranial pulsed ultrasound stimulates intact brain circuits. Neuron. 2010; 66:681-94.
• [39]Min B-K, Bystristky A, Jung K-I, Fischer K, Zhang Y, Maeng L-S et al.. Focused ultrasound-mediated suppression of chemically-induced acute epileptic EEG activity. BMC Neurosci. 2011; 12:23. BioMed Central Full Text
• [40]Yoo S-S, Bystristky A, Lee J-H, Zhang Y, Fischer K, Min B-K et al.. Focused ultrasound modulates region-specific brain activity. Neuroimage. 2011; 56:1267-75.
• [41]Deffieux T, Younan Y, Wattiez N, Tanter M, Pouget P, Aubry J. Low-intensity focused ultrasound modulates monkey visuomotor behavior. Curr Biol. 2013; 23:2430-3.
• [42]King RL, Brown JR, Newsome WT, Pauly KB. Effective parameters for ultrasound-induced in vivo neurostimulation. Ultrasound Med Biol. 2013; 39:312-31.
• [43]Legon W, Sato TF, Opitz A, Mueller J, Barbour A, Williams A et al.. Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans. Nat Neurosci. 2014; 17:322-9.
• [44]Howseman AM, Bowtell RW. Functional magnetic resonance imaging: imaging techniques and contrast mechanisms. 1999.
• [45]Dervishi E, Larrat B, Pernot M, Adam C, Marie Y, Fink M et al.. Transcranial high intensity focused ultrasound therapy guided by 7 TESLA MRI in a rat brain tumour model: a feasibility study. Int J Hyperthermia. 2013; 29:598-608.