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1. Non-invasive opening of BBB by focused ultrasound

Author

Hynynen, K., McDannold, N., Vykhodtseva, N., Jolesz, F. A., Steiger, H.-J., editor, Kuroiwa, T., editor, Baethmann, A., editor, Czernicki, Z., editor, Hoff, J. T., editor, Ito, U., editor, Katayama, Y., editor, Marmarou, A., editor, Mendelow, B. A. D., editor, and Reulen, H.-J., editor

Published
2003
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3. Focus Ultrasound-Induced Blood-Brain Barrier opening enhances anti-pGlu3 Av mAb delivery and amyloid-beta plaque clearance

Author

Bathini, P., Sun, T., Shi, Q., Zhang, Y., Taudte, N., Schenk, M., Hettmann, T., Schilling, S., McDannold, N., Lemere, C.A., and Publica

Abstract

Background. Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance delivery of therapeutic agents to CNS. Our lab has shown that an mAb (07/2a), targeting N-terminally truncated and modified toxic Av species, reduced pGlu3 Av and general Av cerebral plaques in aged APP/PS1dE9 mice. Here, we asked whether FUS-induced BBB opening enhances the delivery of 07/2a mAb and whether it has any additive effect on cognition or plaque clearance. Methods. First, 24 mo-old APP/PS1dE9 mice were i.v. infused with a single dose of 300 µg 07/2a with or without hippocampal FUS sonication (n=5/group) with i.v. infused Optison microbubbles and euthanized 4 or 72 h later; brain levels of antibodies were measured by ELISA. Next, 16 mo-old APP/PS1dE9 mice were treated weekly for 3 weeks with PBS (n=9), 500 µg 07/2a alone (n=9), FUS alone (n=7) or 07/2a + FUS combination (n=6). Behavioral testing in the Water T Maze (WTM) was performed 1-2 weeks later followed by euthanasia. Results. FUS treatment increased 07/2a mAb levels in brain by 5.9-fold 4 hr (41.7 pg/mg for mAb alone, vs. 244 pg/mg mAb+FUS; t=3.48, p

Published
2021

4. Characterization of the diffusion properties of different gadolinium-based MRI contrast agents after ultrasound induced blood–brain barrier permeabilization

Author

Fowlkes, B, Ghanouni, P, Sanghvi, N, Coussios, C, Lyon, Pc, Gray, M, Mannaris, C, Victor, Mds, Stride, E, Cleveland, R, Carlisle, R, Feng, W, Middleton, M, Gleeson, F, Aubry, J, Pauly, Kb, Moonen, C, Vortman, J, Sharabi, S, Daniels, D, Last, D, Guez, D, Levy, Y, Volovick, A, Grinfeld, J, Rachmilevich, I, Amar, T, Zibly, Z, Mardor, Y, Harnof, S, Plaksin, M, Weissler, Y, Shoham, S, Kimmel, E, Naor, O, Farah, N, Paeng, D, Zhiyuan, X, Snell, J, Quigg, Ah, Eames, M, Jin, C, Everstine, Ac, Sheehan, Jp, Lopes, Bs, Kassell, N, Looi, T, Khokhlova, V, Mougenot, C, Hynynen, K, Drake, J, Slayton, M, Amodei, Rc, Compton, K, Mcnelly, A, Latt, D, Kearney, J, Melodelima, D, Dupre, A, Chen, Y, Perol, D, Vincenot, J, Chapelon, J, Rivoire, M, Guo, W, Ren, G, Shen, G, Neidrauer, M, Zubkov, L, Weingarten, Ms, Margolis, Dj, Lewin, Pa, Mcdannold, N, Sutton, J, Vykhodtseva, N, Livingstone, M, Kobus, T, Zhang, Y, Schwartz, M, Huang, Y, Lipsman, N, Jain, J, Chapman, M, Sankar, T, Lozano, A, Yeung, R, Damianou, C, Papadopoulos, N, Brokman, O, Zadicario, E, Brenner, O, Castel, D, Shih-Ying, W, Grondin, J, Zheng, W, Heidmann, M, Karakatsani, Me, Sánchez, Cjs, Ferrera, V, Konofagou, Ee, Yiannakou, M, Cho, H, Lee, H, Han, M, Choi, J, Lee, T, Ahn, S, Chang, Y, Park, J, Ellens, N, Partanen, A, Farahani, K, Airan, R, Carpentier, A, Canney, M, Vignot, A, Lafon, C, Delattre, J, Idbaih, A, Odéen, H, Bolster, B, Jeong, Ek, Parker, Dl, Gaur, P, Feng, X, Fielden, S, Meyer, C, Werner, B, Grissom, W, Marx, M, Weber, H, Taviani, V, Hargreaves, B, Tanaka, J, Kikuchi, K, Ishijima, A, Azuma, T, Minamihata, K, Yamaguchi, S, Nagamune, T, Sakuma, I, Takagi, S, Santin, Md, Marsac, L, Maimbourg, G, Monfort, M, Larrat, B, François, C, Lehéricy, S, Tanter, M, Samiotaki, G, Wang, S, Acosta, C, Feinberg, Er, Kovacs, Zi, Tsang-Wei, T, Papadakis, Gz, Reid, Wc, Hammoud, Da, Frank, Ja, Kim, S, Jikaria, N, Bresler, M, Qureshi, F, Xia, J, Tsui, P, Liu, H, Plata, Jc, Sveinsson, B, Salgaonkar, Va, Adams, M, Diederich, C, Ozhinsky, E, Bucknor, Md, Rieke, V, Mikhail, A, Severance, L, Negussie, Ah, Wood, B, de Greef, M, Schubert, G, Ries, M, Poorman, Me, Dockery, M, Chaplin, V, Dudzinski, So, Spears, R, Caskey, C, Giorgio, T, Costa, Mm, Papaevangelou, E, Shah, A, Rivens, I, Box, C, Bamber, J, ter Haar, G, Burks, Sr, Nagle, M, Nguyen, B, Milo, B, Nhan M., L, Song, S, Zhou, K, Nabi, G, Huang, Z, Ben-Ezra, S, Rosen, S, Mihcin, S, Strehlow, J, Karakitsios, I, Nhan, L, Schwenke, M, Demedts, D, Prentice, P, Haase, S, Preusser, T, Melzer, A, Mestas, J, Chettab, K, Gomez, Gs, Dumontet, C, Werle, B, Marquet, F, Bour, P, Vaillant, F, Amraoui, S, Dubois, R, Ritter, P, Haïssaguerre, M, Hocini, M, Bernus, O, Quesson, B, Livneh, A, Adam, D, Robin, J, Arnal, B, Fink, M, Pernot, M, Khokhlova, Td, Schade, Gr, Wang, Y, Kreider, W, Simon, J, Starr, F, Karzova, M, Maxwell, A, Bailey, Mr, Lundt, Je, Allen, Sp, Sukovich, Jr, Hall, T, Zhen, X, May, P, Lin, Dw, Constans, C, Deffieux, T, Park, E, Ahn, Yd, Kang, Sy, Park, D, Lee, Jy, Vidal-Jove, J, Perich, E, Ruiz, A, Jaen, A, Eres, N, del Castillo, Ma, Myers, R, Kwan, J, Coviello, C, Rowe, C, Crake, C, Finn, S, Jackson, E, Pouliopoulos, A, Caiqin, L, Tinguely, M, Tang, M, Garbin, V, Choi, Jj, Folkes, L, Stratford, M, Nwokeoha, S, Tong, L, Farr, N, D’Andrea, S, Gravelle, K, Chen, H, Lee, D, Hwang, Jh, Tardoski, S, Ngo, J, Gineyts, E, Roux, J, Clézardin, P, Conti, A, Magnin, R, Gerstenmayer, M, Lux, F, Tillement, O, Mériaux, S, Penna, Sd, Romani, Gl, Dumont, E, Sun, T, Power, C, Miller, E, Sapozhnikov, O, Tsysar, S, Yuldashev, Pv, Svet, V, Dongli, L, Pellegrino, A, Petrinic, N, Siviour, C, Jerusalem, A, Cunitz, Bw, Dunmire, B, Inserra, C, Guedra, M, Mauger, C, Gilles, B, Solovchuk, M, Sheu, Twh, Thiriet, M, Zhou, Y, Neufeld, E, Baumgartner, C, Payne, D, Kyriakou, A, Kuster, N, Xiao, X, Mcleod, H, Dillon, C, Payne, A, Khokhova, Va, Sinilshchikov, I, Andriyakhina, Y, Rybyanets, A, Shvetsova, N, Berkovich, A, Shvetsov, I, Shaw, Cj, Civale, J, Giussani, D, Lees, C, Ozenne, V, Toupin, S, Salgaonkar, V, Kaye, E, Monette, S, Maybody, M, Srimathveeravalli, G, Solomon, S, Gulati, A, Bezzi, M, Jenne, Jw, Lango, T, Müller, M, Sat, G, Tanner, C, Zangos, S, Günther, M, Dinh, Ah, Niaf, E, Bratan, F, Guillen, N, Souchon, R, Lartizien, C, Crouzet, S, Rouviere, O, Han, Y, Payen, T, Palermo, C, Sastra, S, Olive, K, van Breugel, Jm, van den Bosch, Ma, Fellah, B, Le Bihan, D, Hernandez-Garcia, L, Cain, Ca, Lyka, E, Elbes, D, Chunhui, L, Tamano, S, Jimbo, H, Yoshizawa, S, Fujiwara, K, Itani, K, Umemura, S, Stoianovici, D, Zaini, Z, Takagi, R, Zong, S, Watkins, R, Pascal-Tenorio, A, Jones, P, Butts-Pauly, K, Bouley, D, Lin, C, Hsieh, H, Wei, K, Garnier, C, Renault, G, Seifabadi, R, Wilson, E, Eranki, A, Kim, P, Lübke, D, Huber, P, Georgii, J, Dresky, Cv, Haller, J, Yarmolenko, P, Sharma, K, Celik, H, Guofeng, L, Qiu, W, Zheng, H, Tsai, M, Chu, P, Webb, T, Vyas, U, Walker, M, Zhong, J, Waspe, Ac, Hodaie, M, Yang, F, Huang, S, Zur, Y, Assif, B, Aurup, C, Kamimura, H, Carneiro, Aa, Rothlübbers, S, Schwaab, J, Houston, G, Azhari, H, Weiss, N, Sosna, J, Goldberg, Sn, Barrere, V, Jang, Kw, Lewis, B, Wang, X, Suomi, V, Edwards, D, Larrabee, Z, Hananel, A, Rafaely, B, Debbiny, Re, Dekel, Cz, Assa, M, Menikou, G, Mouratidis, P, Pineda-Pardo, Ja, de Pedro, Mda, Martinez, R, Hernandez, F, Casas, S, Oliver, C, Pastor, P, Vela, L, Obeso, J, Greillier, P, Zorgani, A, Catheline, S, Solovov, V, Vozdvizhenskiy, Mo, Orlov, Ae, Chueh-Hung, W, Sun, M, Shih, Tt, Chen, W, Prieur, F, Pillon, A, Cartron, V, Cebe, P, Chansard, N, Lafond, M, Seya, Pm, Bera, J, Boissenot, T, Fattal, E, Bordat, A, Chacun, H, Guetin, C, Tsapis, N, Maruyama, K, Unga, J, Suzuki, R, Fant, C, Rogez, B, Afadzi, M, Myhre, Of, Vea, S, Bjørkøy, A, Yemane, Pt, van Wamel, A, Berg, S, Hansen, R, Angelsen, B, and Davies, C

Subjects
Settore FIS/07
Published
2017

5. Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound

Author

Kobus, T., Vykhodtseva, N., Pilatou, M., Zhang, Y., McDannold, N., Kobus, T., Vykhodtseva, N., Pilatou, M., Zhang, Y., and McDannold, N.

Abstract

Contains fulltext : 171451.pdf (publisher's version ) (Closed access), The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue.

Published
2016

6. Update on Clinical Magnetic Resonance-Guided Focused Ultrasound Applications

Author

Kobus, T., McDannold, N., Kobus, T., and McDannold, N.

Abstract

Item does not contain fulltext, In this review, several clinical applications of magnetic resonance (MR)-guided focused ultrasound (FUS) are updated. MR-guided FUS is used clinically for thermal ablation of uterine fibroids and bone metastases. Thousands of patients have successfully been treated. Transcranial MR-guided FUS has received CE certification for ablation of deep, central locations in the brain. Thermal ablation of specific parts of the thalamus can result in relief of the symptoms in a number of neurological disorders. Several approaches have been proposed for ablation of prostate and breast cancer and clinical trials should show the potential of MR-guided FUS for these and other applications.

Published
2015

7. Testing the Efficacy of Contrast‐Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation

Author

Fischer, K., Ohori, S., Meral, F. C., Uehara, M., Giannini, S., Ichimura, T., Smith, R. N., Jolesz, F. A., Guleria, I., Zhang, Y., White, P. J., McDannold, N. J., Hoffmeister, K., Givertz, M. M., and Abdi, R.

Abstract

One of the key unmet needs to improve long‐term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast‐enhanced ultrasonography (CEUS). The efficacy of CEUSin detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MPwas demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MPfollowing antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MPdecline observed in the allografts. High‐resolution MPmapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next‐generation imaging approaches to diagnose transplant rejection. High‐resolution perfusion mapping using contrast‐enhanced ultrasound detects transplant rejection.

Published
2017
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11. Image-guided neurosurgery at Brigham and Women's Hospital

Author

Dimaio, S.P., primary, Archip, N., additional, Hata, N., additional, Talos, I., additional, Warfield, S.K., additional, Majumdar, A., additional, Mcdannold, N., additional, Hynynen, K., additional, Morrison, P.R., additional, Wells, W.M., additional, Kacher, D.F., additional, Ellis, R.E., additional, Golby, A.J., additional, Black, P.M., additional, Jolesz, F.A., additional, and Kikinis, R., additional

Published
2006
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23. Magnetic resonance imaging-guided focused ultrasound synovectomy.

Author

Foldes, Karoly, Hymymen, Kullerve, Shortkroff, Sonya, Winalski, Carl S., Collucci, Vincent, Koskinen, Seppo K., McDannold, Nathan, Jolesz, Ferenc, Foldes, K, Hynynen, K, Shortkroff, S, Winalski, C S, Collucci, V, Koskinen, S K, McDannold, N, and Jolesz, F

Subjects
MAGNETIC resonance imaging, SYNOVECTOMY, SYNOVIAL membranes surgery
Abstract

Objective: To investigate the feasibility of magnetic resonance imaging (MRI)-guided high power focused ultrasound (FUS) to perform synovectomy noninvasively.Methods: Five New Zealand white male rabbit knees with experimentally induced arthritis underwent MRI-guided thermal surgery by high power (60 W/10 s) sonication. Evidence of tissue coagulation was monitored during the procedure and confirmed by gross and microscopic evaluation and MRI.Results: Partial synovectomy was performed in five animals. Necrotized synovial tissue was observed on gross and microscopic evaluation. Visible signal intensity alterations including high signal intensity on T2-weighted (T2W) images and lack of contrast-enhancement on T1-weighted (T1W) post-contrast, post-sonication images were characteristic and reproducible.Conclusion: Our results demonstrate the ability of high power sonication to destroy synovial tissue in vivo. [ABSTRACT FROM AUTHOR]

Published
1999
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25. Noninvasive thermal ablation of hepatocellular carcinoma by using magnetic resonance imaging-guided focused ultrasound

Author

Jolesz, F.A., Hynynen, K., McDannold, N., Freundlich, D., and Kopelman, D.

Abstract

A number of minimally invasive methods have been tested for the thermal ablation of liver tumors as an alternative to surgical resection. The use of focused ultrasound transducers to ablate deep tumors offers the first completely noninvasive alternative to these techniques. By increasing the flexibility of this technology with modern phased-array transducer design and by combining it with magnetic resonance imaging for targeting and online guidance, a powerful tool results with the potential to offer treatment to a larger population of patients, to reduce trauma to the patient, and to reduce the cost of treatment. In this article, we review previous work with focused ultrasound in the liver and recent experimental results with magnetic resonance imaging guidance.

Published
2004
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29. Laser-induced thermotherapy of cerebral neoplasia under MR tomographic control

Author

Joachim Kettenbach, Kuroda, K., Hata, N., Morrison, P., Mcdannold, N. J., Gering, D., Saiviroonporn, P., Zientara, G. P., Black, P. Mcl, Kikinis, R., and Jolesz, F. A.

Subjects
medicine.medical_specialty, Palliative treatment, Laser-induced thermotherapy, Interventional magnetic resonance imaging, business.industry, Interstitial laser, Image subtraction, Heat deposition, medicine, T1 weighted, Surgery, Temperature sensitive, sense organs, Radiology, Nuclear medicine, business
Abstract

SummaryThe purpose of this study was to monitor interstitial laser therapy (LITT) in palliative treatment of brain tumours by using temperature-sensitive MRI sequences and image-processing techniques in realtime. Three consenting patients with recurrent gliomas were treated with LITT (3–4.5 W, 3–6 min). Temperature sensitive monitoring was performed either by T1 weighted fast spin echo (FSE) sequences, combined with pixel subtraction, optical flow (OF) computation, or by spoiled gradient recalled (SPGR) sequences used for chemical shift-based imaging. Both sequences were applied at 0.5 T (Signa SRGE Medical System, Milwaukee, Wl, USA). Pixel subtraction identified thermal changes in brain tumours, but could not evaluate the temperature values as chemical-shift based imaging. OF computation displayed the predicted course of thermal changes and revealed that the rate of heat deposition can be anisotropic, which may be related to heterogeneous tumour structure and/or vascularisation.Local tumour control was ...

48. Non-Invasive Blood-Brain Barrier Disruption Using Acoustic Holography With a Clinical Focused Ultrasound System.

Author

McDannold N, Zhang Y, Fletcher SM, Wen PY, Reardon DA, Golby AJ, and Livingstone M

Subjects
Animals, Rats, Transducers, Rats, Sprague-Dawley, Male, Holography methods, Blood-Brain Barrier diagnostic imaging, Blood-Brain Barrier radiation effects, Phantoms, Imaging
Abstract

Objective: Holographic methods can be used with phased array transducers to shape an ultrasound field. We tested a simple method to create holograms with a hemispherical 1024-element phased array transducer and explored how it could benefit ultrasound-mediated blood-brain barrier (BBB) disruption., Methods: With this method, individual acoustic simulations for each element of the transducer were simultaneously loaded into computer memory. Each element's phase was systematically modulated until the combined field matched a desired pattern. The method was evaluated with a 220 kHz transducer being tested clinically to enhance drug delivery via BBB disruption. The holograms were evaluated in a tissue-mimicking phantom and in vivo in experiments disrupting the BBB in rats and in a macaque. We also explored whether this approach could mitigate secondary reflections from the skull using simulations of transcranial focusing in clinical treatments of transcranial sonication for BBB disruption., Results: This approach can enlarge the focal volume in a patient-specific manner and could reduce the number of sonication targets needed to disrupt large volumes, improve the homogeneity of the disruption, and improve our ability to detect microbubble activity in tissues with low vascular density. Simulations suggest that the method could also mitigate secondary reflections during transcranial sonication.

Published
2024
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49. Cavitation monitoring, treatment strategy, and acoustic simulations of focused ultrasound blood-brain barrier disruption in patients with glioblastoma.

Author

McDannold N, Wen PY, Reardon DA, Fletcher SM, and Golby AJ

Subjects
Humans, Retrospective Studies, Middle Aged, Temozolomide administration & dosage, Temozolomide therapeutic use, Male, Antineoplastic Agents, Alkylating administration & dosage, Female, Drug Delivery Systems, Aged, Acoustics, Adult, Computer Simulation, Blood-Brain Barrier metabolism, Glioblastoma diagnostic imaging, Glioblastoma drug therapy, Brain Neoplasms diagnostic imaging, Brain Neoplasms drug therapy, Microbubbles, Magnetic Resonance Imaging methods
Abstract

Purpose: We report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of this retrospective analysis were to compare MRI-based measures of BBB disruption and vascular damage to the exposure levels, acoustic emissions data, and acoustic simulations. We also simulated the cavitation detectors., Methods: Monthly BBB disruption (BBBD) was performed using a 220 kHz hemispherical phased array focused ultrasound system (Exablate Neuro, InSightec) and Definity microbubbles (Lantheus) over 38 sessions in nine patients. Exposure levels were actively controlled via the cavitation dose obtained by monitoring subharmonic acoustic emissions. The acoustic field and sensitivity profile of the cavitation detection system were simulated. Exposure levels and cavitation metrics were compared to the level of BBBD evident in contrast-enhanced MRI and to hypointense regions in T2*-weighted MRI., Results: Our treatment strategy evolved from using a relatively high cavitation dose goal to a lower goal and longer sonication duration and ultimately resulted in BBBD across the treatment volume with minimal petechiae. Subsonication-level feedback control of the exposure using acoustic emissions also improved consistency. Simulations of the acoustic field suggest that reflections and standing waves appear when the focus is placed near the skull, but their effects can be mitigated with aberration correction. Simulating the cavitation detectors suggest variations in the sensitivity profile across the treatment volume and between patients. A correlation was observed with the cavitation dose, BBBD and petechial hemorrhage in 8/9 patients, but substantial variability was evident. Analysis of the cavitation spectra found that most bursts did not contain wideband emissions, a signature of inertial cavitation, but biggest contribution to the cavitation dose - the metric used to control the procedure - came from bursts with wideband emissions., Conclusion: Using a low subharmonic cavitation dose with a longer duration resulted in BBBD with minimal petechiae. The correlation between cavitation dose and outcomes demonstrates the benefits of feedback control based on acoustic emissions, although more work is needed to reduce variability. Acoustic simulations could improve focusing near the skull and inform our analysis of acoustic emissions. Monitoring additional frequency bands and improving the sensitivity of the cavitation detection could provide signatures of microbubble activity associated with BBB disruption that were undetected here and could improve our ability to achieve BBB disruption without vascular damage., Competing Interests: Declaration of competing interest NM's laboratory has received research support from InSightec. AJG is the site PI for the clinical study supported by InSightec., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Published
2024
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50. The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening.

Author

Fletcher SP, Zhang Y, Chisholm A, Martinez S, and McDannold N

Subjects
Animals, Rats, Ultrasonic Waves, Rats, Sprague-Dawley, Male, Sonication methods, Microbubbles, Blood-Brain Barrier metabolism, Blood-Brain Barrier radiation effects, Drug Delivery Systems
Abstract

Objective. Pulsed focused ultrasound (FUS) can deliver therapeutics to the brain by using intravenous microbubbles (MBs) to open the blood-brain barrier (BBB). MB emissions indicate treatment outcomes, like BBB opening (harmonics) and damage (broadband). Typically, a pulse repetition frequency (PRF) of 1 Hz is used, but the effect of PRF on MBs is not fully understood. We investigated the effect of PRF on MB activity and tracer delivery. Approach. The effect of PRF (0.125, 0.25, 0.5, 1, and 2 Hz) on MB activity was monitored through harmonic and wideband emissions during FUS sonications of the rat brain at 274.3 kHz. BBB opening was quantified through fluorescence imaging to estimate the concentration of Trypan Blue (TB) dye following a 75-pulse FUS exposure for PRFs of 1 and 0.25 Hz. Main results. At a fixed acoustic pressure, the percentage change in maximum harmonic amplitude compared to the control (PRF = 1 Hz) decreased with increasing PRF, with a median change of 73.8% at 0.125 Hz and -38.3% at 2 Hz. There was no difference in the pressure threshold for broadband emissions between PRFs of 0.25 and 1 Hz. PRF = 0.25 Hz, led to a 68.2% increase in the mean concentration of TB measured after FUS, with a 53.9% increase in the mean harmonic sum, compared with PRF = 1 Hz. Harmonic emissions-based control at PRF = 0.25 Hz yielded similar TB delivery, with less damage at histology, compared with 1 Hz. Significance. For a fixed number of FUS pulses, reducing the PRF was shown to increase the magnitude of harmonic emissions and TB delivery, but not the threshold for broadband emissions. While further research is necessary to understand the mechanisms involved, these results may be useful to improve clinical safety margins and sensitivity to detecting small harmonic signals from cavitating MBs., (© 2024 Institute of Physics and Engineering in Medicine.)

Published
2024
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