Ultrasound in combination with the introduction of microbubbles into the vasculature effectively opens the blood brain barrier (BBB) to allow the passage of therapeutic agents. Increased permeability of the BBB is typically demonstrated with small-molecule agents (e.g., 1-nm gadolinium salts). Permeability to small-molecule agents, however, cannot reliably predict the transfer of remarkably larger molecules (e.g., monoclonal antibodies) required by numerous therapies. To overcome this issue, we developed a magnetic resonance imaging analysis based on the ΔR 2 * physical parameter that can be measured intraoperatively for efficient real-time treatment management. We demonstrate successful correlations between ΔR 2 * values and parenchymal concentrations of 3 differently sized (18 nm–44 nm) populations of liposomes in a rat model. Reaching an appropriate ΔR 2 * value during treatment can reflect the effective delivery of large therapeutic agents. This prediction power enables the achievement of desirable parenchymal drug concentrations, which is paramount to obtaining effective therapeutic outcomes.

Background: Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. With drug treatment only partially efficient, new treatments are being developed. Objectives: The goal of this study was to demonstrate the feasibility of non-thermal focused-ultrasound (FUS) to induce tremor-suppression in an ET rat model. Methods: Harmaline-induced tremor rats were treated with FUS along the inferior olivary (IO) system. EMG was recorded continuously during treatment in order to quantify FUS-induced tremor suppression. T2-weighted MRI was performed immediately following treatment and periodically thereafter. Results: FUS treatment at an intensity of 27.2 W/cm(2) (Isppa) induced significant reduction of tremor in 12 out of 13 ET rats. Tremor frequency was reduced from 6.2 +/- 2.8 to 2 +/- 1 Hz, p < 0.0003. In 6 of the 12 responding rats, tremor was completely suppressed. Response duration was 70 +/- 61s, on average. FUS induced motor response, depicted as movement of the tail and/or the limbs synchronized with the FUS sonication, was also demonstrated both in ET rats and in naive rats when treated in the medulla oblongata region. Conclusions: These results demonstrate the feasibly for obtaining significant tremor reduction or tremor suppression induced by non-thermal, non-invasive, reversible focused-ultrasound. (C) 2018 Elsevier Inc. All rights reserved.

Background: Focused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging.Methods: A novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives.Results: With a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator.Conclusions: The estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice.

Overcoming the resistant to change - is there a strategy that could bring all the different stakeholders to combine and align efforts?

Background: Focused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging. Methods: A novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives. Results: With a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator. Conclusions: The estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice. *Correspondence: michael.schwenke@mevis.fraunhofer.de 1Fraunhofer Institute for Medical Image Computing MEVIS, Am Fallturm 1, 28359 Bremen, Germany Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Schwenke et al. Journal of Therapeutic Ultrasound (2017) 5:20 Page 2 of 14 Background Focused ultrasound (FUS) is increasingly entering clinical routine as an alternative treatment method in different indications [1]. Current clinical FUS applications mostly target static organs. FUS treatment of abdominal targets that move with the respiration of the patient (e.g. the liver) is not yet an available option in clinical routine due to the lack of treatment systems supporting this functionality. The current clinical use cases of FUS for moving abdominal organs include both palliative treatments and patients for whom resection is impossible due to the position of the malignant tissue or co-morbidities [2, 3]. Treating targets in abdominal organs like the liver with FUS is challenging [2]: The target moves with the respiration and may be partially blocked by the ribcage for parts of the respiratory cycle. Real-time temperature monitoring of the treatment needs to be performed using MR thermometry [4]. For moving organs this is even more complicated than for static organs. Thermometry using ultrasound imaging is possible [5], but not yet available for clinical use. To tackle these challenges, in today’s FUS treatment of moving abdominal targets, the motion of the target needs to be controlled under anesthesia [6–8]: One option is to stop the respiration (apnea) for the duration of active ultrasound application and afterwards let the respiration normalize before starting the next sonication. This procedure, however, results in long treatment duration and the need for general anesthesia. Another approach that is close to clinical application is respiratory-gated sonication [9]. Thereby, the therapeutic ultrasound is active during the respiratory cycle only when the target is detected to be in a certain position. This approach allows for a treatment without general anesthesia, but suffers also from overly long treatment duration due to the reduction of the FUS duty cycle. In the long run, FUS can become competitive to other thermal ablation techniques as radio-frequency ablation (RFA), microwave ablation (MWA), laser-induced thermotherapy (LITT), and cryoablation. It may even become an alternative to resection and radiosurgery.Whether FUS can be competitive to these well-established techniques strongly depends on results of current and future clinical application of the treatment. In our research we hypothesize that the full potential of FUS in moving organs can be unleashed only with dedicated computer support in planning and control of the treatment. In this paper we present our efforts from the past years in developing model-based software support for FUS in the moving liver. An integrated system has been developed that shall allow to treat the liver during motion. Here we focus in particular on the system design and on our framework for in-silico testing of the system. We also describe our efforts to simplify the translation of research results to prototypes that may be used in clinical studies. A major effort in developing a software system for treatment planning and control is quality assurance (QA): Making sure that the system does what it is supposed to do (efficacy), and, most importantly, that it does no harm (safety). For safety-critical systems estimates for the proportion of life cycle costs spent on QA and testing go up to 80% [10]. Thus, for industry, the hurdle to develop a FUS treatment system with motion compensation is high because of the risk that FUS may in the end turn out to not be competitive to the above-mentioned established ablation methods. From the viewpoint of research and development, changing currently available clinical FUS treatment systems to make them capable of motion-compensated FUS is difficult as the clinically approved systems are not open for extensions and are subject to closed specifications. Also, introducing changes to the certified systems means that any validation needs to be re-performed. For systems of such complexity the effort required for a change in the system grows drastically the later a defect is detected or a new feature should be incorporated (exponential cost-of-change curve [11]). In our work, we define the requirements and design specification in an open way to simplify extension and collaboration. We aim at reducing the necessary QA efforts by code generation and extensive continuous testing. A virtual system using numerical FUS simulations has been developed and used for first-stage numerical experimental validation. Using this virtual system, automatic execution of system tests is possible and system design parameter studies can be performed to analyze the efficiency of the system. This way, the effort for actual real-world experimentation and validation can be reduced allowing for a more changeable system. Contribution In this article we report on our development of a FUS treatment system including motion compensation with the long-term goal of meeting the requirements for a “Class III Medical Product”. The system allows to perform a single-target motion-compensated sonication during respiratory motion. It is specified and defined in a generic way abstracting from actual hardware components. A first implementation of the system has been performed with clinically available hardware, i.e. an MR device (GE Healthcare Systems, Chicago, USA) and FUS device (Conformal Bone System 2100, InSightec Ltd., Tirat Camel, Israel). To facilitate the translation of FUS research results to the clinic, the treatment system is defined open for extensions and the use with hardware devices of other vendors and may be used as a research platform for FUS experimentation. Schwenke et al. Journal of Therapeutic Ultrasound (2017) 5:20 Page 3 of 14 A virtual system using numerical FUS simulations is presented and used for first-stage numerical experimental validation. The treatment system interacts with the emulation in the same way it does with real hardware and is provided with realistic data that is influenced by its control commands. A comprehensive numerical FUS simulation during respiratory motion (previously described in detail [12]) is used to predict the treatment effects that would happen in a real FUS experiment. Using this virtual system, automatic execution of system tests is possible and system design parameter studies are performed to analyze the efficiency of the system. One advantage of this approach is that the numerical experiments can easily be observed in the simulation whereas physical measurements in real-world experiments are challenging, time-consuming, and require a lot of resources. Related work Motion-compensation for FUS. The challenges for FUS treatment systems imposed by respiratory motion have been addressed by several stud

Introduction: The novel Trans-Fusimo Treatment System (TTS) is designed to control Magnetic Resonance guided Focused Ultrasound (MRgFUS) therapy to ablate liver tumours under respiratory motion. It is crucial to deliver the acoustic power within tolerance limits for effective liver tumour treatment via MRgFUS. Before application in a clinical setting, evidence of reproducibility and reliability is a must for safe practice.Materials and methods: The TTS software delivers the acoustic power via ExAblate-2100 Conformal Bone System (CBS) transducer. A built-in quality assurance application was developed to measure the force values, using a novel protocol to measure the efficiency for the electrical power values of 100 and 150W for 6s of sonication. This procedure was repeated 30 times by two independent users against the clinically approved ExAblate-2100 CBS for cross-validation.Results: Both systems proved to deliver the power within the accepted efficiency levels (70-90%). Two sample t-tests were used to assess the differences in force values between the ExAblate-2100 CBS and the TTS (p> 0.05). Bland-Altman plots were used to demonstrate the limits of agreement between the two systems falling within the 10% limits of agreement. Two sample t-tests indicated that TTS does not have user dependency (p> 0.05).Conclusions: The TTS software proved to deliver the acoustic power without exceeding the safety levels. Results provide evidence as a part of ISO13485 regulations for CE marking purposes. The developed methodology could be utilised as a part of quality assurance system in clinical settings; when the TTS is used in clinical practice.

Axial T1 projection showing the relation of VIM target 3 mm medial and anterior to pyramidal tract and medial lemniscus respectively

The application of FUS in abdominal organs such as the liver or the kidneys is impeded by a number of complications. One of the most challenging is organ motion due to breathing. To achieve ablation in a target within a moving organ the FUS system has to be steered to focus on the same anatomical position. We present a prototypical system that tracks the motion of an ex vivo ovine liver via diagnostic ultrasound (US) and adjusts the focal spot to a fixed anatomical position.

Organ motion is a major problem for Focused Ultrasound Surgery (FUS) of liver tumors. We present a liver phantom mimicking human respiratory motion (20 mm range, 3 − 7 s/cycle) and the evaluation of an ultrasound-tracked steered FUS system on that phantom. Temperature curves are recorded while sonicating in moving and static phantom. The temperature curves correlate well and show the ability of the system to compensate breathing like motion.

The movement of the target challenges the application of high intensive focused ultrasound (HiFU/MRgFUS) for the treatment of malignancies in moving abdominal organs such as liver and kidney. Moreover, the anatomical location of the lesion is often behind the rib cage. The physiology of the organs, the dynamic and complex blood perfusion impairs the energy disposition in the tissue due to the heat transfer within the organ. To explore the full potential of extracorporeal FUS to safely and precisely destroy tissue in the depth of a moving organ requires sophisticated software and advanced hardware. In the EU project FUSIMO (http://www.fusimo.eu) a software demonstrator for the patient specific planning of FUS in the liver has been developed in order to empower the physician to perform safe, effective and efficient ablation of tumours and to facilitate prediction of the outcome. The new EU project TRANS-FUSIMO (http://www.trans-fusimo.eu) aims at the translation of this software demonstrator into a fully integrated system for the FUS treatment of the liver.

Non-invasive ablation and hyperthermia treatments of abdominal organs using High Intensity Focused Ultrasound (HIFU) still impose severe challenges. Especially for liver and kidney treatments, the target motion and accessibility over the entire respiratory cycle make the application of HIFU difficult. To allow for a safe, effective, and efficient treatment, detailed planning and monitoring of the intervention is needed. Current general-purpose physics simulation software cannot fulfill the real-time requirements of the therapy-monitoring application. Our goal is to improve this by numerical simulation to allow for fast and accurate treatment planning and real-time detection of motion-induced risks during HIFU-therapy.

Focused ultrasound surgery (FUS) is a non-invasive method for tissue ablation that has the potential for complete and controlled local tumour destruction with minimal side effects. The treatment of abdominal organs such as the liver, however, requires particular technological support in order to enable a safe, efficient and effective treatment. As FUS is applied from outside the patient's body, suitable imaging methods, such as magnetic resonance imaging or diagnostic ultrasound, are needed to guide and track the procedure. To facilitate an efficient FUS procedure in the liver, the organ motion during breathing and the partial occlusion by the rib cage need to be taken into account in real time, demanding a continuous patient-specific adaptation of the treatment configuration. Modelling the patient's respiratory motion and combining this with tracking data improves the accuracy of motion predictions. Modelling and simulation of the FUS effects within the body allows the use of treatment planning and has the potential to be used within therapy to increase knowledge about the patient status. This article describes integrated model-based software for patient-specific modelling and prediction for FUS treatments of moving abdominal organs.

Poster: ECR 2013 / C-1255 / FUSIMO: A prototype for patient-specific prediction of focused ultrasound surgery in moving organs by: J. Strehlow 1, S. Haase2, J. Jenne3, T. Lango4, Y. Levy5, A. Loeve6, A. Melzer7, M. Muller8, A. Napoli9, G. Samei10, M. Schwenke1, C. Tanner10, H. Tiesler1, C. Tiu11, T. Preusser1; 1Bremen, Deutschland/DE, 2Bremen/DE, 3Heidelberg/DE, 4Trondheim/NO, 5TIrat Carmel/IL, 6Delft/NL, 7Dundee/UK, 8Brno/CZ, 9Rome/IT, 10Zurich/CH, 11Campina /RO