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© The Author(s). 2018
- Published: 15 May 2018
Oral Presentations
O1 Neuroinflammation after disrupting the blood brain barrier with pulsed focused ultrasound and microbubbles imaged by 18F-DPA-714 PET and MRI
Zsofia I. Kovacs, Georgios Z. Papadakis, Tsang-Wei Tu, Sanhita Sinharay, William C. Reid, Bobbi Lewis, Dima A. Hammoud, Joseph A. Frank
National Institutes of Health, Bethesda, Maryland, United States
Correspondence: Zsofia I. Kovacs
via 1.5f0 ultra harmonic acoustic emission detection for every single pulse (9 focal points, 120 sec/9 focal points – striatum, 120 sec/4 focal points – hippocampus) using an 825 kHz hydrophone with a single-element spherical FUS transducer (center frequency: 589.636 kHz; focal number: 0.8; aperture: 7.5 cm; RK-100, FUS Instruments, Toronto, Ontario, Canada). T2* map were created from multiecho gradient echo sequence at 3T (Achieva, Philips Healthcare, Andover, MA) through the rat brain with TE=7 msec, echo train length 5 and echo spacing 7 and Tr=1500 msec. T2* maps were created by fitting signal intensity at each voxel to a single exponential fit with in-house software and histogram analysis was performed on volume of interests (VOI). Static microPET/CT scans emission data was acquired 30-60 min after injection of 18F-DPA-714. VOIs were drawn in the targeted areas and uptake was compared to the contralateral unaffected side. Uptake values were normalized to cerebellum. increase in uptake for both regions compared to normal brain. The neuroinflammatory changes persisted for at least 14 days after 2 weekly sonications. The coefficient of variation for PET scans was <10%. This corresponded to Iba1 activation visible on histology. Figure 2 contains normalized histograms from VOI for Group 2 and Group 3 rats derived from pFUS+MB treated (ipsilateral) and contralateral brain that shows a shift to lower T2* values for sonicated regions. Kovacs, Z. I., et al. (2017). 'Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation.' Proc Natl Acad Sci U S A 114(1): E75-E84. O'Reilly, M. A. and K. Hynynen (2012). 'Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller.' Radiology 263(1): 96-106. et al. 2016; Downs, in vivo. T2, T2* and Gd-enhanced T1-weighted images were obtained by 3.0T MRI (Achieva, Philips Healthcare, Andover, MA), T2, T2* and diffusion tensor imaging (DTI) were performed by 9.4T MRI (Bruker, Billerica, MA). Parameters for DTI: 3D spin echo EPI; TR/TE 700 ms/37 msec; b-value 800 sec/mm2 with 17 encoding directions; voxel size 200 μm (isotropic). Fractional anisotropy (FA) and the asymmetry of magnetization transfer ratio (MTRasym) were derived for mapping structural injury and glucose levels. Rats received ~1.1 mCi of 18F-FDG Arvanitis, C. D., et al. (2016). 'Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model.' J Neurosurg 124(5): 1450-1459. Downs, M. E., et al. (2015). 'Long-Term Safety of Repeated Blood-Brain Barrier Opening Wu S-K, Chu P-C, Chai WY, Kang S-T, Tsai C-H, Fan C-H, Yeh C-K, Liu H-L. Characterization of Different Microbubbles in Assisting Focused Ultrasound-Induced Blood-Brain Barrier Opening. Sci Rep. 2017; 7. Available from: http://www.nature.com/articles/srep46689 doi:10.1038/srep46689 via via an via immunoblotting, and histological staining will be used to identify transfected cells via HPLC. via Western blotting. Immunoblotting and histological staining confirmed the expression of reporter genes in neuronal cells. 1,4, Vasileios Askoxylakis2, Yutong Guo1, Jonas Kloepper2, Meenal Datta2, Miguel Bernabeu3, Dai Fukumura2, Nathan McDannold5, Rakesh Jain2 in vivo and in silico data demonstrate significant changes in the tumor microenvironment after FUS-BBB/BTB disruption. The most notable changes included: i) increase in BBB/BTB permeability, ii) transition to convection dominated drug transport, and iii) increased cellular transmembrane transport in endothelial cells and stroma cells. Sensitivity analysis showed that the system has become more amenable to interventions, suggesting that FUS can lead to the development of new therapeutic strategies to treat brain tumors. f0 = 0.5MHz was attached to a stereotactic system and used to deliver ultrasoundenergy into the target brain region. One piezocomposite hydrophone with resonant frequency at 0.75MHz was built to acquire the signals emitted from stimulatedmicrobubbles. A feedback control algorithm was implemented in LabVIEW to quantify the area under curve (AUC) within sub-/ultra-harmonic bands during theultrasound exposure and to adjust the focal pressure accordingly based on the difference between current AUC and a desired threshold. Initial f0, 1.5f0 as a function offocal pressure and microbubble concentration. Due to the significant response detected at 1.5in vitro. Next an in-vivo study was performed in a rat model toevaluate the acoustic emissions and the feasibility of real-time control of the AUC at a target level. Acoustic emissions from a bolus injection and continuous infusionwere evaluated. For bolus injection, a fixed pressure level of 0.54 MPa was applied, while for infusion experiment, the feedback control was used to control the AUC atvarious levels. Evans blue dye was used as an indicator of BBB opening. in vitro, with the greatestchanges occurring at 0.75 MHz (1.5f0 and tested with a continuous infusion of microbubbles. Successful maintenance of the AUC at different target value was achieved invivo at multiple locations in the brain, and BBB opening was confirmed as leakage of Evans Blue at the target locations (Fig. 1D). 1, Cyril Lafon2, Jean-Louis Mestas2, Shin-ichiro Umemura1 A classic method for source localization is triangulation. The localization of the cavitation cloud is deduced from the delays obtained between threereceptors with known positions. In our case, the receptors are PVDF hydrophones. Two confocal transducers are emitting a pulse at 1.1 MHz in order to generate cavitation in the optical field of a high-speed camera. The signals from the three hydrophones were recorded during the US pulse on a digital oscilloscope and the delays between the hydrophones were calculated by finding the delay maximizing the inter-correlation between the recorded signals. The source position calculated from thedelays was finally superimposed over the images from the camera (Fig. 1). The positions calculated with this method were compared to the positions of the clouds visually estimated. The mean discrepancy was calculated. The method was firstly applied using the signals with full frequency bandwidth. Then, the post-processing operation was repeated after keeping only the bandwidth of 200 kHz around the sub-harmonic frequency (550 kHz). Also, simulations are performed to evaluate the versatility of the method in various test cases. Notably, spatial spreading of the source, source separation and the influence of the hydrophones repartition are evaluated. 1, Martijn de Greef1, Rémi Berriet2, Chrit Moonen1, Mario Ries1 1, Matthieu Guedra1, Jean-Christophe Bera1, Wen-Shiang Chen2, Hao-Li Liu3, Claude Inserra1 1, Eilon Hazan1,3, Omer Naor1, Michael Plaksin1, Inbar Brosh1, Noam Maimon2, Yoav Levy2, Eitan Kimmel1, Itamar Kahn3, Shy Shoham1 Shoham S, Krupa S, Hazan E, Naor O, Levy Y, Maimon N, Brosh I, Kimmel E, Kahn I. A126 Research platform for rodent studies of wavefront engineered ultrasonic neuromodulation. J Ther Ultrasound. 2016; 4(Suppl 1):31. Available from: https://jtultrasound.biomedcentral.com/articles/10.1186/s40349-016-0076-5 2,1, David Moore3, Matthew Eames3, John Snell3,4, James Larner2, Neal Kassell3,4 1, Ben Lucht, Rohan Ramdoyal1, Samuel Gunaseelan1, Tyler Portelli1, Ping Wu1, Kullervo Hynynen1,2 Rise of nations windows 10 download. 1, Wayne Brisbane1, Stella Whang2, Yak-Nam Wang3, Kayla Gravelle2, Venu Pillarisetty4, W. Conrad Liles5, Vera Khokhlova3, Michael Bailey3, Tatiana D. Khokhlova2, Joo Ha Hwang2 in vivo. We characterized the long-term immune response to BH RCC tumor ablation in a ratmodel. 2, Aaron Prodeus1, 2, Jean Gariepy1, 2, Kullervo Hynynen1, 2, David Goertz1, 2 1, Tsang-Wei Tu1, Scott R. Burks1, Bobbie K. Lewis1, Joseph A. Frank1,2 1,2, Jeremy Vion1,2, Loïc DAUNIZEAU1,2, Christopher Bawiec2, Guillaume BOUCHOUX1, 3, Nicolas Sénégond4, Jean-Yves Chapelon1,2, Alexandre CARPENTIER3,5 in vivo on 10 pigs and monitored under real-time multi-planar magnetic resonance thermometry (MRT) (Fig. 1). in vivo. Further investigations are ongoing to improve the robustness of the CMUTdevices and increase the treatment volumes. This project was supported by CarThera, the French National Research Agency (ANR, 2010) and Single InterministerialFund (FUI, 2013). The object of this study is to provide a method for imaging, in real time, the HIFU beam inside an acoustically propagative medium using beamforming in an ultrasound scanner.Novelty and advantagesThe novelty of the method can be found in its implementation of beamforming in an ultrasound scanner, which is analogous to the backward reconstruction using time reversal. The advantage of this method is its real-time imaging capability owing to digital parallel processing of the scanner. Further advantage is simplicity of the imaging system without requiring additional equipment aside from an ultrasound scanner and an ultrasound array serving as a time-reversal mirror. via plane-wave beamforming. Evaluations: The feasibility of the method was evaluated using either the time-reversal reconstruction or the beamforming reconstruction, with and without HIFU beam aberrations. First, in the experiment in water without HIFU beam aberrations, performance of the method was demonstrated in comparison with the reference field obtained by numerical calculation of the forward propagation using the Rayleigh integral and hydrophone scanning. Then, in the experiment with HIFU beam aberrations induced by heterogeneous hydrogel, HIFU beam visibility was evaluated with referred to the HIFU pressure field measured by hydrophone scanning. Burks S, Nagle M, Kim S, Milo B, Frank J. A90 Low-intensity ultrasound prolongs lifetimes of transplanted mesenchymal stem cells. J Ther Ultrasound. 2016; 4(Suppl 1):31. Available from: https://jtultrasound.biomedcentral.com/articles/10.1186/s40349-016-0076-5 Dai H, Chen F, Yan S, Ding X, Ma D, Wen J, Xu D, Zou X. In Vitro and In Vivo Investigation of High-Intensity Focused Ultrasound (HIFU) Hat-Type Ablation Mode. Med Sci Monit. 2017; 23:3373-3382. Available from: https://www.medscimonit.com/abstract/index/idArt/902528 DOI: 10.12659/MSM.902528 in situ utilizing simplified propagation models and calibration power measurements. in vitro setup used to provide a validation for the image-based approach. In particular, an acoustic power meter (Omega, Ohmic instruments Easton, MD) was modified to allow the measurement of the insertion loss due to a slab of tissue-mimicking phantom between the DMUA and the tip of the cone (treated as the target). The TM phantom was fabricated from animal skin bovine gelatine, graphite,1-propanol, glutaraldehyde, and deionized water. Absorption of the phantom is predominately due to the presence of graphite and was determined to be 0.6 and 1.0dB/cm/MHz for two 4-mm disk-shaped slaps. Two modes of the imaging were used to characterize the FUS beam propagation through the tissue: 1) Synthetic-aperture(SA) imaging, which provides larger field of view (FoV) to characterize the propagation medium, and 2) Single-transmit focus (STF), which provides specific feedback about the interactions between the FUS beam and the tissue in its path to the target. The STF imaging is performed using the same beamforming parameters of the intended therapeutic HIFU beam, but at diagnostic levels and with sub-microsecond pulse duration. HIFU was applied at 4 different frequencies (2.4 to 4.2 MHz in stepsof 0.6 MHz). HIFU shots of 1-sec durations were used and repeated 4 times. SA and STF images were collected before, during and after the application of therapeutic HIFU. The STF frame rate was 400 fps, which was helpful to fully characterize the incidence of cavitation and/or instability in the power measurement. in vitro at multiple frequencies. The method has been applied for the estimation of the focusing gain in vivo. As described, STF imaging of the phantom slab allowed for measuring the beam dimensions and the FUS interaction with the tissue and could be used in future studies to extract details of an inhomogeneous medium to provide accurate estimates of the focusing gain (or heating rate). Further validation of the calculated heating rate will be performed in vivo by measuringtemperature with thermocouples in the vicinity of the focus. in situ’ in variousorgans. At this stage, the neoplasm is generally spherical in shape while, conventionally, focused ultrasound (FUS) treatment involves ‘raster’ scanning the formation ofthe HIFU lesions in the ROI, an approach that will generally not conform to the spherical tumor geometry. This may lead to two major undesirable effects: large gaps or overlaps at the tumor margins (physical spacing isn’t optimized) and between individual lesions, or significant ‘lesion-to-lesion’ interaction creating uncertainty in the shape, size and extent of the subsequent lesions due to the remnant effect of previously laid lesions. Furthermore, the gaps between adjacent lesions may have a seeding effect, leading to further growth of malignancies due to the untreated sections. To avoid lesion interactions, several authors suggested a pre-defined time delay betweenlesions or change in exposure parameters. The former results in unnecessary treatment delays while the latter involves capacious real-time computations for optimizing the treatment (dynamically computing thermal dose) as well as remotely and frequently switching on/off high power equipment. In order to overcome these deficiencies, we propose a method for determining the optimal lesion arrangement within any arbitrary tumor size and shape, based on an extension of the bubble packing algorithm first described by Shimada in 1995 [1]. The original algorithm was extended to allow lesions to take any arbitrary position andorientation within the specified tumor volume, and evaluated on spherical and ellipsoidal tumor models. 1, Jonathan Caloone1, Anthony Kocot1, Cyril Huissoud2 ex vivo model. The effectiveness of this HIFU device applied to the perfused placental unit must be studied in a preclinical animal study under conditions similar to those in humans before starting a clinical trial. Here, we report a feasibility study using a monkey model of pregnancy. The 3 objectives of this work were (i) to evaluate the feasibility and reproducibility of HIFU lesions in the placenta of pregnant monkeys 2,1, Raj Aravalli1, Emad S. Ebbini1 1, Christian Aurup1, Carlos J. Sierra Sánchez1, Julien Grondin1, Wenlan Zheng1, Vincent Ferrera2, Elisa E. Konofagou1,3 in vivo in vivo in vitro that these limitations may be due to the conventional ultrasound sequences used to disrupt the BBB. These sequences consist of long-pulses emitted at a slow rate and generate a mixture of both desired and undesired cavitation activities. We have recently developed and tested a new low pressure rapid short-pulse (RaSP) sequence in vivo efficiency and safety of ultrasound-mediated drug delivery to the brain. in vivo in C57BL/6 mice would improve the efficiency and safety of brain drug delivery. We compared our RaSP sequence (peak-negative pressure: 400 kPa; pulse length (PL): 5 cycles; pulse repetition frequency (PRF): 1.25 kHz; burst length: 10 ms) to the current gold standard, conventional sequence at the same acoustic pressure (PL: 10,000 cycles; PRF: 0.5 Hz; burst length: 10 ms). Fluorescently-tagged (Texas Red) 3 kDa dextran and microbubbles were intravenously injected in mice while sonicating the left hippocampus with a 1 MHz focused ultrasound transducer. A 7.5 MHz passive cavitation detector captured the microbubble acoustic emissions. The relative dose and distribution of the drug were quantified by calculating the normalised optical density (NOD, average increase in fluorescence in the targeted area normalised by the control) and the coefficient of variation (COV, standard deviation over the average fluorescence intensity in the targeted region). Safety was assessed by haematoxylin and eosin (H&E) histological staining. Nappoli A, Zaccagna F, Catocci G, Giulia B, Caliolo G, Andrani F, Catalano C. Magnetic resonance guided focused ultrasound surgery (MRgFUS) treatment of osteoid osteoma: a prospective development study. J Ther Ultrasound. 2015; 3(Suppl 1): O44. Available from: https://jtultrasound.biomedcentral.com/articles/10.1186/2050-5736-3-S1-O44 Greillier P, Ankou B, Bessière, Zorgani A, Pioche M, Kwiecinski W, Magat J, Melot-Dusseau S, Lacoste R, Quesson B, Pernot M, Catheline S, Chevalier P, Lafon C. A75 Trans esophageal HIFU for cardiac ablation: first experiment in non-human primate. J Ther Ultrasound. 2016; 4(Suppl 1):31. Available from: https://jtultrasound.biomedcentral.com/articles/10.1186/s40349-016-0076-5 1, Takashi Azuma1, Kosuke Minamihata2, Satoshi Yamaguchi1, Shinya Yamahira1, Etsuko Kobayashi1, Mariko Iijima1, Yoshikazu Shibasaki1, TeruyukiNagamune1, Ichiro Sakuma1 1. Kawabata K et al. Jpn J Appl Phys 2005; 44: 4548. 2. Ishijima A et al. Ultrasonics 2016; 69: 97–105. 3. Lee YH et al. Biochem Biophys Res Commun 2013; 441: 1011–1017. 4. Wang CH et al. Biomaterials 2012; 33: 1939–1947. [1] Arnal et al, Appl Phys Lett, 101 1-5, 2012 [2] Robin et al, IEEE IUS, 2015 [3] Sarvazyan et al, Acoust Phys 55 630–7, 2009 [4] Luong et al, Sci Rep 6 36096, 2016 [5] Montaldo et al, Appl Phys Lett 2004 (No Image Selected) in vivo model for HCM. Under ketamin/zylazine IP anesthesia, contrast agent was infused at a rate of 5μL/min/kg (tail vein catheter). The shaved and depilated left thorax was aimed at with a cardiac phased array (10S, Vivid 7, GE Healthcare) to center on the left ventricular myocardium. In this arrangement a 19 mm diameter single element therapy transducer was co-aligned to aim at a registered region of interest in the field of view of the 10S array. For therapy 10-cycle tone bursts at 1.5 MHz, 4 repetitions at 0.25 ms pulse interval, i.e. 4.0 kHz PRF, were sent every 8 heartbeats, aligned with trigger end systole (RR/3, using ECG gating). Peak negative free field pressures of 4 MPa were used to induce cavitation for 10 min. Therapy and sham therapy groups were followed up with MP administered at 0, 3, 6 and 24 hours after ultrasound exposure. Specifically, 30 mg/kg was chosen as high dose while 1 mg/kg was used as low dose alternative. Myocardial wall thickness 24 hours after therapy, measured from echocardiography was used to gauge the effect of initial myocardial swelling. White blood cell count was carried out 24 hours after therapy. Hearts were removed after 4 weeks and examined for evidence of the MP treatment effect. Histological sections with Masson’s trichrome staining were quantitatively analyzed for extent of fibrosis, i.e. tissue scarring. Imaging protocol was: TR=600ms, TE=36ms, slice thickness=5mm, resolution=1.6*1.6mm2, matrix=54*128, EPI factor=9. Acquisition time=8.4s. Two sets of images with opposite polarity of DEG were used to quantify the displacement in each measurement. Ten measurements of ARFI were scanned before and immediately after HIFU sonication. T-test was used to determine whether tissue displacements have significantly changed. Temperature rise was monitored by GREduring HIFU sonication. The protocol was: TR=29ms, TE=10ms with the same FOV and resolution. The ambient temperature was 19°C. T2w image was acquired after HIFU sonication with TR=5000ms, TE=89ms, resolution=0.8*0.8 mm2, matrix=108*256. p = 0.18 from 1, Xue Feng1, Helen L. Sporkin1, Jeff Elias2, Kim Butts-Pauly3, Craig H. Meyer1 [1] Plata et al. “A feasibility study on monitoring the evolution of apparent diffusion coefficient decrease during thermal ablation,” Med. Phys., 42(8), 5130–5137, 2015 [2] Smith et al. “Reduced field of view MRI with rapid, B1-robust outer volume suppression,” Magn. Reson. Med., 67(5), 1316–1323, 2012. in vitro in vitro to deliver drugs into cells. Through these studies, it was discovered that several mechanisms of trans-membrane drug delivery exist and that they are highly dependent on the acoustic parameters, microbubble conditions, and the cell-type used. Despite promising results from these study, the advancement from single cell-bubble interactions to clinical use has not been made. This gap in development is largely because the underlying mechanism of trans-membrane drug delivery under high flow condition and for a large population of cells, remains poorly understood and poorly controlled. Our study explores the ultrasound and microbubble-mediated trans-membrane drug delivery efficiency and safety to a monolayer of endothelial cells using a state-of-theart physiologically-relevant cultivation system under different ultrasound exposure conditions. In the end, we will evaluate the critical question on whether safe transmembrane drug delivery can be achieved in such a complex, physiologically relevant environment. 1,2, Melissa Lin2, Eric O'Neill2, Oliver D. Kripfgans2, 1, Renny T. Franceschi3, 4, Andrew J. Putnam4, Mario L. Fabiilli1, 2 in vivo model via CD31 immunohistochemical staining on days 7 and 14. ex vivo. The ability to non-invasively stimulate and inhibit the PNS with FUS would allow clinicians an alternative therapeutic modality to treat peripheral neuropathy, as current treatment procedures can generate systemic side effects or require invasive procedures. In this study, we aim to show that FUS can elicit excitatory effects targeting the PNS and generate downstream physiological responses. ex vivo mouse limbs alongside the sciatic nerve and exposed to FUS stimulation. A force balance was used to determine the acoustic radiation force generated by the transducer to estimate the tissue deformation in the focal region. To confirm neural activity at the single-unit level, a via FUS was shown capable of eliciting both observable leg twitching and measurable EMG responses when using the following FUS parameters: 0.2-5.7 MPa, 35-100% DC (continuous wave), 0.1-1kHz PRF, 0.8-10.5 ms stimulation duration. Increasing the pressure and DC raised the average peak-to-peak EMG response along with the success rate (Fig. 1). Varying the PRF or stimulation duration did not have a significant effect on response. Both delay and peak-to-peak EMG responses for FUS stimulation were found to be comparable to direct electrical stimulation of the sciatic nerve. Mice stimulated with efficacious parameters did not display any significant deviation in behavior compared to the control group or baseline values. The blinded histology study did not detect any damage for the stimulated group, only for the positive control. In in vivo. This demonstrates that FUS can be a non-invasive alternative to conventional therapeutic methods. Specific FUS parameters has been identified for successful and safe stimulation. Future work to explore the potential mechanisms of generation of the action potential will dictate the FUS parameters to translate this technique to clinical applications. 1,2 1,2, A. Dupre1, 2, Y. Chen2, D. Perol2, J. Vincenot1, M. Rivoire1, 2 Melodelima D, Dupre A, Vincenot J, Chen Y, Perol D, Rivoire M. A49 Clinical experience of intra-operative High Intensity Focused Ultrasound in patients with colorectal liver metastases. Results of a Phase II study. J Ther Ultrasound. 2016; 4(Suppl 1):31. Available from: https://jtultrasound.biomedcentral.com/articles/10.1186/s40349-016-0076-5. 1, G. G. Powathil2, P. Ziegenhein1, J. Ijaz3, I. Rivens1, M. Chaplain4, U. Oelfke1, G. ter Haar1 in vitro FUS experiments, (2) to verify FUS simulation using measured temperature distributions, (3) to predict the cellular effects of combination treatments. via mitotic catastrophe. The CAM was compared to results from experiments designed to characterise the response of HCT116 cells [1] G. Powathil et al., Semin Cancer Biol, (30, p.13–20), 2015 [2] B. Clarke, Ultrasound Med Biol, (21, p. 353–363), 1995 Sankin, G. N. & Zhong, P. (2006), ‘Interaction between shock wave and single inertial bubbles near an elastic boundary’, Phys. Rev. E 74, 046304. M can only provide a plane distribution of cavitation, which is not conducive to clinical diagnosis. PAM based on a hemispherical array has been used for three-dimensional (3D) vascular imaging with high resolution in the brain, but it is not suitable for treatment monitoring of other biological tissues, such as liver and kidney. This means that 3D PAM based on an area array for omnibearing monitoring of ultrasound therapy is required. The objective of this work is to develop a three-dimensional super-resolution passive imaging technique for microvessel and an omnibearing monitoring of ultrasound therapy in real time. 1, L. Sebeke2, M. Baragona3, A. Elevelt4, R. Maessen3, D. Bošnački1, H. Ten Eikelder1 1,2, A. Wright2, D. Goertz1,2 in vivo 2, 1, S. Sethuraman2, B. Cheng1, J. Kruecker2, R. Chopra1 in vivo in vivo rabbit muscle under normal respiration and perfusion, strain-based ultrasound thermometry is feasible in the mild hyperthermia range. 1, S. Wang1, T. Payen1, E. Konofagou1,2 in vivo environment and characterize tumor at different depth for better tumor localization and identification before and after HIFU treatment. Figure 2 shows the HIFU sequence consisting of high-intensity short pulses to generate bubble clouds, named “trigger pulses”, and following moderate-intensity long bursts for the enhancement of the ultrasonic heating, named “heating bursts”. The focal point of the trigger pulse was electronically scanned at each corner of a regular hexagon 3 mm each side and a ring focal region was generated employing a sector vortex method in the heating burst exposure to cover the six foci of the trigger pulse for the volumetric cavitation-enhanced heating. The total acoustic power for the trigger pulse and heating burst were 1800 and 90 W, respectively. The duration and interval time for trigger pulses at each focal point were 25 and 3 μs, respectively. The trigger pulses were laterally scanned for four times. For heating bursts, the duration and interval time for trigger pulses at each focal point were 5 ms and 4 μs, respectively. The focal spot was scanned 5 times. The subtotal durations of trigger pulses and heating bursts were 0.67 and 50 ms, respectively. Immediately after the end of the heating bursts, a 2-ms interval time was reserved for ultrasonic imaging with plane wave transmissions at a frequency of 1.88 MHz. Ultrasonic RF data were also acquired during the HIFU exposure for the passive coagulation detection. 1,2, B. He1,2, N. Deng1,2, X. Chen1,2, S. Chen1,2, C. Chin1,2 in situ focal point of FUS, and therefore, it is possible to compensate for navigational error due to beam distortion by the heterogeneous human body. However, ultrasound still cannot assist in determining correct ultrasound dosage in a realistic clinical setting. Microbubbles has been investigated as a biocompatible, internal “probe” to convert a local parameter to an echo characteristic that can be measured externally. We accessed the main challenge is that the multiple acoustic parameters are not easily isolated from the multiple measureable characteristics of the echo signals (such as frequency shifts and harmonic component). In order to isolate the multiple factors (such as attenuation and perfusion rate) contributing to measurable echo characteristics, we sought to exploit the highly specific behaviors of microbubble destruction when exposed to intense ultrasound. This paper reports a feasibility study of a pre-treatment scheme to determine effective attenuation and other relevant parameters and subsequently compensate for them during the actual therapeutic procedure. in situ beam intensity without controlling the microbubble concentration. The data sets of destruction curves obtained with attenuating layers were matched to the un-attenuated reference data set using a multi-parameter fitting algorithm (Fig. 3). The resulting fitted beam intensity was found to match closely the actual values, verified by independent measurement of attenuation. The errors of in-situ intensity, and compensation to the therapy planning applied, before the actual course of treatment is applied. This study also demonstrated some capabilities of the in-house designed 2D array therapy system. Particularly interesting is that an arbitrary treatment ROI can be exposed in less than 32 ms. In this study the scanning speed of the treatment focus was exploited to ensure that the entire ROI is exposed evenly in between excessive imaging events. in vitro cytotoxicity by ultrasound treatment for 5 mins with the intensity of 5W/cm 2 after MCF-7 and HeLa tumor cells were incubated with sonosensitizer Protoporphyrin IX (PpIX) and Oxy-NGV. Then the singlet oxygen level, as the major cytotoxic agent, was imaged using Singlet Oxygen Sensor Green (SOSG) in both cell-free model and intracellular scenario. Meanwhile the oxygen level was also tested by dissolved oxygen meter compared with conventional SDT method. These studies were repeated in both normal oxygen level and hypoxia condition. in vivo. in vivo study was performed using the xenograft mouse models of human liver and prostate cancers. Hep3B human cancer cells and DU145 human prostate cancer cells (2.0×106) were injected on flanks of athymic nude mice. Tumors were allowed to grow to 8-10 mm size and then separated into the following treatment groups: HIFU alone, PEI (50%Etoh, 50 μl) alone, PEI+HIFU (50%Etoh, 50 μl), and sham. Tumor sizes were measured by caliper every day and a veterinary diagnostic ultrasound system was used pre-treatment, 5 days, and 12 days’ post- treatment. Tumor volumes were calculated from the ellipsoid formula V=πabc/6, where a, b, c are tumor sizes in three orthogonal directions. Tumors were surgically removed and fixed using 10% formaldehyde solution. Samples were sent for H&E staining with a single blinded pathologist, and live/dead percentages of tumor cross sections were determined at 5 and 12 days post treatment. Cryogenic-Scanning Electron Microscopy (Cryo-SEM) was also used to capture membrane disruption post HIFU+PEI exposure on DU145 prostate cancer cells. 1, S. Song1, M. Kajimoto1, J. Chen1, R. Fu1, K. Morrison2, G. W. Keilman2, C. H. Miao1,3 via a midline incision. Next, using contrast US to confirm placement and perfusion, we catheterized a specific branch of the portal vein. Just prior to therapeutic US exposure, the inferior vena cava was temporarily occluded. Then US exposure and infusion of a solution containing pGL4 plasmid and phospholipid microbubbles (MBs) were initiated simultaneously. Therapeutic US was delivered 1, Q. Zhu1, X. Dong1, Z. Chen1, Z. Liu1, F. Xie2O2 Long term effects of pulsed focused ultrasound and microbubbles detected by multivariate imaging modalities
Zsofia I. Kovacs, Tsang-Wei Tu, Georgios Z. Papadakis, William C. Reid, Dima A. Hammoud, Joseph A. Frank
National Institutes of Health, Bethesda, Maryland, United States
Correspondence: Zsofia I. Kovacs
O3 Characterization of different microbubbles in assisting focused ultrasound-induced blood-brain barrier opening
Sheng-Kai Wu1, Po-Chun Chu2, 3, Wen Yen Chai3, 4, Shih-Tsung Kang5, Chih-Hung Tsai3, Ching-Hsiang Fan5, Chih-Kuang Yeh5, Hao-Li Liu3
1Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; 2Department of Research and Development, NaviFUS corp, Taipei, Taiwan; 3Department of Electrical Engineering, Chang-Gung University, Taoyuan City, Taiwan; 4Department of Diagnostic Radiology and Intervention, Chang-Gung Memorial Hospital, Taoyuan City, Taiwan; 5Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
Correspondence: Sheng-Kai Wu
O4 Development of an A-Synuclein (SNCA)-based mouse model for Parkinson's disease by ultrasound-guided CNS delivery
Chung-Yin Lin1, Yu-Chien Lin2, Hao-Li Liu2
1Institute for Radiological Research, Chang Gung University, Taoyuan City, Taiwan; 2Department of Electrical Engineering, Chang Gung University, Taoyuan City, Taiwan
Correspondence: Chung-Yin Lin
1Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; 2Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; 3Centre for Medical Informatics, University of Edinburgh, Edinburgh, UK; 4Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; 5Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Correspondence: Costas Arvanitis
O6 Acoustic emissions during blood-brain barrier disruption with focused ultrasound and real-time feedback control under infusion administration of microbubbles – feasibility study in rodent model
Chenchen Bing1, Debra Szczepanski1, Imalka Munaweera1, Yu Hong1, Ian Corbin2, Rajiv Chopra1,2
1Radiology, UT Southwestern Medical Center, Dallas, Texas, USA; 2Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, Texas, USA
Correspondence: Chenchen Bing
Maria Eleni Karakatsani1, Tara Kugelman1, Shutao Wang1, Karen Duff3, Elisa E. Konofagou1,2
1Biomedical Engineering, Columbia University, New York, New York, USA; 2Radiology, Columbia University, New York, New York, USA; 3Pathology and Cell Biology, Columbia University, New York, New York, USA
Correspondence: Maria Eleni Karakatsani
1Graduate School of Biomedical Engineering - Umemura-Yoshizawa Laboratory, Tohoku University, Sendai, Miyagi, Japan; 2LabTAU, INSERM U1032, Université deLyon, Lyon, France
Correspondence: Maxime Lafond
1UMC Utrecht, Utrecht, Netherlands; 2Imasonic SAS, Voray-sur-l'Ognon, France
Correspondence: Pascal Ramaekers
1Univ Lyon, Université Lyon 1, INSERM, LabTAU, F-69003, LYON, France, Lyon, France; 2Department of Physical Medicine & Rehabilitation, National TaiwanUniversity Hospital, Taipei, Taiwan; 3Department of Electrical Engineering, Chang Gung University, Taoyuan City, Taiwan
Correspondence: Corentin Cornu
1Department of Biomedical Engineering, Technion I.I.T, Haifa, Israel; 2Insightec LTD, Tirat HaCarmel, Israel; 3Department of Medicine, Technion I.I.T., Haifa, Israel
Correspondence: Steve Krupa
O12 Image-guided dual-target brain stimulation on mouse by array ultrasound
Guofeng Li, Jiehan Hong, Qiuju Jiang, Peitian Mu, Ge Yang, Congzhi Wang, Weibao Qiu, Hairong Zheng
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
Correspondence: Guofeng Li
1LabTAU, INSERM, Lyon, France; 2Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia, USA; 3FUS Foundation, Charlottesville, Virginia, USA; 4Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, USA
Correspondence: Cyril Lafon
1Sunnybrook Research Institute, Toronto, Ontario, Canada; 2Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Correspondence: Ben Lucht
1Department of Urology, University of Washington, Seattle, Washington, USA; 2Department of Gastroenterology, University of Washington, Seattle, Washington, USA; 3Center for Industrial and Medical Ultrasound, University of Washington, Seattle, Washington, USA; 4Department of Surgery, University of Washington, Seattle, Washington, USA; 5Department of Medicine, University of Washington, Seattle, Washington, USA
Correspondence: George R. Schade
1University of Toronto, Toronto, Ontario, Canada; 2Sunny brook Research Institute, Toronto, Ontario, Canada
Correspondence: Sharshi Bulner
1Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland, USA; 2National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA
Correspondence: Kee W. Jang
1LabTAU, INSERM, U1032, Lyon, Rhone-Alpes, France; 2Univ Lyon, Université Lyon 1, Lyon, F-69003, France; 3CarThera Research Team, Brain and Spine Institute, Paris, France; 4Vermon SA, Tours, France; 5Department of Neurosurgery, Assistance Publique, Hopitaux de Paris, Pitie Salpetriere, Paris, France
Correspondence: William Apoutou N'Djin
O20 Real-time HIFU beam imaging using beamforming in an ultrasound scanner
Kazuhiro Matsui1, Françoise CHAVRIER2, 4, Takashi Azuma3, Ichiro Sakuma1, 5, William Apoutou N'Djin2, 4, Rémi Souchon2,4
1Engineering, The University of Tokyo, Tokyo, Japan; 2LabTAU, INSERM unité 1032, Lyon, France; 3Medicine, The University of Tokyo, Tokyo, Japan; 4Univ Lyon, Université Lyon 1, Lyon, France; 5Medical Device Development and Regulation Research Center, Tokyo, Japan
Correspondence: Kazuhiro Matsui
O22 Impact of microbubble-enhanced radiofrequency ablation of rabbit liver
Zhong Chen, Xueyan Qiao
Department of Ultrasound, Xinqiao Hospital, The Third Military Medical University, Chongqing, China
Correspondence: Zhong Chen
O24 Image-based predicition of focusing gain in situ using dual-mode ultrasound arrays
Brogan T. McWilliams, Dalong Liu, Emad S. Ebbini
Electrical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
Correspondence: Brogan T. McWilliams
O25 An automatic approach to lesion planning for robotic HIFU
Tom Williamson, Scott Everitt, Ranjaka De Mel, Sunita Chauhan
Mechanical and Aerospace Engineering, Monash University, Melbourne, Victoria, Australia
Correspondence: Tom Williamson
1LabTAU - U1032, INSERM, Lyon, Rhône Alpes, France; 2CHU Croix Rousse, LYON, France
Correspondence: David Melodelima
1Electrical and Computer Engineering, University of Minnesota, Minneapolis, Minnesota, USA; 2Siemens, Seattle, Washington, USA
Correspondence: Dalong Liu
1Biomedical Engineering, Columbia University, New York, New York, USA; 2Neuroscience, Columbia University, New York, New York, USA, 3Radiology, Columbia University, New York, New York, USA
Correspondence: Shih-Ying Wu
O32 Transoesophageal HIFU for cardiac ablation: experiments on beating hearts
Paul Greillier1, Bénédicte Ankou2, Ali Zorgani1, Francis Bessière2, Fabrice Marquet3, Julie Magat3, Sandrine Melot-Dusseau4, Romain Lacoste4, Bruno Quesson3, Mathieu Pernot5, Philippe Chevalier2, Cyril Lafon1, 6
1LabTau - U1032, INSERM, LYON, Rhône, France; 2Hôpital Louis-Pradel, Lyon, France; 3IHU-LIRYC - CHU Bordeaux, Pessac, France; 4Station de primatologie -CNRS- UPS846, Rousset, France; 5Institut Langevin - Ondes et Images - ESPCI ParisTech, CNRS UMR 7587, Paris, France; 6University of Virginia, Charlottesville, Virginia, USA
Correspondence: Paul Greillier
O33 In-vivo investigation of the combination of focused ultrasound and radiotherapy, using photoacoustic imaging as aplanning and monitoring tool
Marcia M. Costa, Anant Shah, Ian Rivens, Tuathan O'Shea, Carol Box, Jeff Bamber, Gail ter Haar
Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, UK
Correspondence: Marcia M. Costa
1The University of Tokyo, Tokyo, Japan; 2Kyushu University, Fukuoka, Japan
Correspondence: Ayumu Ishijima
O35 Dual mode time reversal cavity for US shockwave therapy and 3D imaging
J. Robin1,2, B. Arnal1, M. Tanter1, M. Pernot1
1Institut Langevin, Paris, France; 2Université Paris 7, Paris, France
Correspondence: J. Robin
O36 The effects of steroids on the myocardial reduction induced by myocardial cavitation-enabled therapy (MCET)
Y. I. Zhu1, X. Lu2, C. Dou2, D. L. Miller2, O. D. Kripfgans2, 1
1O.D. Kripfgans, Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA; 2Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA
Correspondence: Y. I. Zhu
1Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA; 2Neurological Surgery, University of Virginia Hospital, Charlottesville, Virginia, USA; 3Radiology, Stanford University, Palo Alto, Virginia, USA
Correspondence: Steven P. Allen
O41 Selection of MR-HIFU hyperthermia treatment sites based on MR thermometry evaluation in healthy volunteers
Satya V.V.N. Kothapalli1, Michael Altman2, Ari Partanen3, Lifei Zhu1, Galen Cheng1, H. Michael Gach2, William Straube2, Dennis Hallahan2, Hong Chen1,2
1Biomedical Engieering, Washington University in Saint Louis, Saint Louis, Missouri, USA; 2Department of Radiation Oncology, Washington University in St. Louis, Saint Louis, Missouri, USA; 3Clinical Science MR Therapy, Philips, Andover, Massachusetts, USA
Correspondence: Satya V.V.N. Kothapalli
1Applied Physics Program, University of Michigan, Ann Arbor, Michigan, USA; 2Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA; 3School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA; 4Department of Biomedical Engineering, University of Michigan, AnnArbor, Michigan, USA
Correspondence: Alexander Moncion
O46 The safety and feasibility of high intensity focused ultrasound in treatment of resistant hypertension
P. You
State Key Laboratory of Ultrasound Engineering in Medicine Co-founded by Chongqing and the Ministry of Science and Technology,Chongqing Key Laboratory of Ultrasound in Medicine and Engineering,College of Biomedical Engineering,Chongqing Medical University, Chongqing, China
1The College of Biomedical Engineering, Chongqing Medical University, Chongqing, Chongqing, China; 2Haifu Hospital of the First Hospital Affiliated Hospital, Chongqing Medical University, Chongqing, China
1LabTAU - U1032, INSERM, Lyon, Rhône Alpes, France; 2Centre Leon Berard, Lyon, France
Correspondence: D. Melodelima
O49 Catheter-directed thrombolysis of deep vein thrombosis enhanced by intraclot microbubbles and ultrasound: A clinical study
Q. Zhu1, S. GAO1, G. Dong2, M. Guo1, F. XIE3
1Department of Ultasound, XinQiao Hospital,Third Military Medical University, Chongqing, China; 2Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; 3Internal Medicine Cardiology, University of Nebraska Medical Center, Omaha, NE, China
Correspondence: Q. Zhu
S. Yeo1, Y. Kim2, 3, H. Lim3, 4, H. Rhim3, S. Jung4, 5, N. Hwang5
1Radiology, University Hospital of Cologne, Cologne, Germany; 2Radiology, Mint Hospital, Seoul, Korea; 3Radiology and Center for Imaging Science, Samsung Medical Center, Seoul, Korea; 4Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea; 5Biostatistics and Clinical Epidemiology Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
Correspondence: S. Yeo
1Joint Department of Physics, The Institute of Cancer Research, Sutton, UK; 2Swansea University, Swansea, UK; 3Bristol University, Bristol, UK; 4St. Andrew's University, St. Andrews, UK
Correspondence: S. C. Brueningk
O53 Lithotripter shock wave interaction with a bubble near various bio-material
S. Ohl1, E. Klaseboer1, A. Szeri2, B. Khoo3
1Institute of High Performance Computing, Singapore, Singapore; 2University of California, Berkeley, Berkeley, California, USA; 3National University of Singapore, Singapore, Singapore
Correspondence: S. Ohl
O54 Three-dimensional passive acoustic localization and mapping for cavitation: a preliminary study
S. Lu, X. Du, M. Wan
Biomedical Engineering, Xi’an Jiaotong University, Xi’an, China
Correspondence: S. Lu
1Eindhoven University of Technology, Eindhoven, Netherlands; 2University Hospital Cologne, Cologne, Germany; 3Department of Multiphysics & Optics, Philips Research Eindhoven, Eindhoven, Netherlands; 4Department of Oncology Solutions, Philips Research Eindhoven, Eindhoven, Netherlands
Correspondence: D. Modena
1University of Toronto, Toronto, Ontario, Canada; 2Sunnybrook Research Institute, Toronto, Ontario, Canada
Correspondence: C. Acconcia
Correspondence: S. Zhang
1Department of Radiology, UT Southwestern Medical Center, Dallas, Texas, USA; 2Ultrasound Imaging & Interventions, Philips Research North America, Cambridge, Massachusetts, USA
O62 Changes in backscatter of liver tissue due to thermal heating can be used for guiding focused ultrasound ablations
V. Barrere1,2, D. Melodelima1,2
1LabTAU, INSERM, Lyon, France; 2Université Claude Bernard, Lyon 1, Lyon, France
Correspondence: V. Barrere
1BME, Columbia University, New York, New York, USA; 2Radiology, Columbia University, New York, New York, USA
Correspondence: Y. Han
1Biomedical Engineering, Shenzhen University, Shenzhen, Guangdong, China; 2National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen, China
Correspondence: Y. Peng
O66 Enhanced sonodynamic therapy using oxygen-rich nano gas vesicle
Y. Yang, X. Hou, L. Sun
Interdisciplinary Division of Biomedical Engineering, Hong Kong Polytechnic University, Hong Kong, China
Correspondence: Y. Yang
1Center for Immunity and Immunotherapies, Seattle Children's Research, Seattle, Washington, USA; 2Sonic Concepts Inc., Bothell, Washington, USA; 3Pediatrics, University of Washington, Seattle, Washington, USA
Correspondence: J. Harrang