Non-invasive transcranial brain ablation with high-intensity focused ultrasound.

The idea to ablate brain tissue with high-intensity focused ultrasound (HIFU) in a highly precise and localized manner is relatively old. For HIFU tissue ablation, ultrasound (US) waves are concentrated to a focal point. Due to US absorption, the focal area will be heated and consequently thermally destroyed. The spatial accuracy of the non-invasive procedure and the sharp delineation of the induced tissue lesions have led to the term 'focused ultrasound surgery' (FUS). The major obstacle for HIFU ablation in the brain is the skull bone, which absorbs most of the US energy and disturbs the focused US field. The development of large-sized phased array US transducers and adaptive focusing techniques based on computed tomography images have allowed these difficulties to be overcome. With the combination of FUS and MR-imaging and MR-thermometry (MR-guided Focused Ultrasound Surgery, MRgFUS), real-time therapy guidance and control has been established. The safety, feasibility and effectiveness of transcranial MRgFUS were investigated in four initial clinical studies including 4 to 15 patients each. In the first study, which dealt with the treatment of inoperable recurrent glioblastoma, MR was used to monitor localized tissue heating, but no tissue ablation was possible due to technical restrictions of the treatment setup. With improved equipment, the precise induction of thermal lesions in the target area was achieved in studies on neuropathic pain and essential tremor. An instantaneous and persistent significant improvement of disease symptoms was observed in most patients. However, there were serious adverse effects in two cases, where intracranial hemorrhages appeared due to the induction of cavitation. Based on these encouraging clinical results, more extensive clinical studies have been initiated. Transcranial MRgFUS is a fast-growing field of neurological research with high clinical potential.

Crushed rephased orthogonal slice selection (CROSS) for simultaneous acquisition of two orthogonal proton resonance frequency temperature maps.

PURPOSE: To evaluate a novel imaging sequence termed crushed rephased orthogonal slice selection (CROSS) that uses the available time in long echo time (TE) gradient echo (GRE) imaging-as employed for proton resonance frequency (PRF) shift thermometry-to simultaneously acquire two orthogonal magnetic resonance imaging (MRI) temperature maps around the target region. MATERIALS AND METHODS: The CROSS sequence encodes a second orthogonal slice between excitation and data readout in long-TE imaging and applies dedicated crusher (CR) gradients to separate the signals from the two slices. Numerical simulations of the Bloch equations and phantom experiments were performed to analyze the MR signal. In phantom and in vivo experiments with two domestic pigs, the applicability of the CROSS sequence for temperature mapping of thermal therapies with focused ultrasound and laser was studied. RESULTS: A successful separation of the signals from the two slices was achieved for CR dephasing lengths approaching the in-plane resolution. In the two animal experiments, CROSS temperature mapping could be successfully demonstrated at a temporal resolution of 2-3 seconds and a temperature uncertainty of 3-4K. CONCLUSION: At the expense of a reduced signal in the overlap of the two slices, the CROSS sequence achieves an improvement of temporal resolution by 50%, without requiring further acceleration techniques such as parallel imaging, over conventional sequential GRE sequences employing the same repetition time as the CROSS sequence acquires two slices within one repetition interval.

High-intensity focused ultrasound: principles, therapy guidance, simulations and applications.

In the past two decades, high-intensity focused ultrasound (HIFU) in combination with diagnostic ultrasound (USgFUS) or magnetic resonance imaging (MRgFUS) opened new ways of therapeutic access to a multitude of pathologic conditions. The therapeutic potential of HIFU lies in the fact that it enables the localized deposition of high-energy doses deep within the human body without harming the surrounding tissue. The addition of diagnostic ultrasound or in particular MRI with HIFU allows for planning, control and direct monitoring of the treatment process. The clinical and preclinical applications of HIFU range from the thermal treatment of benign and malign lesions, targeted drug delivery, to the treatment of thrombi (sonothrombolysis). Especially the therapy of prostate cancer under US-guidance and the ablation of benign uterine fibroids under MRI monitoring are now therapy options available to a larger number of patients. The main challenges for an abdominal application of HIFU are posed by partial or full occlusion of the target site by bones or air filled structures (e.g. colon), as well as organ motion. In non-trivial cases, the implementation of computer based modeling, simulation and optimization is desirable. This article describes the principles of HIFU, ultrasound and MRI therapy guidance, therapy planning and simulation, and gives an overview of the current and potential future applications.

A long arm for ultrasound: a combined robotic focused ultrasound setup for magnetic resonance-guided focused ultrasound surgery.

PURPOSE: Focused ultrasound surgery (FUS) is a highly precise noninvasive procedure to ablate pathogenic tissue. FUS therapy is often combined with magnetic resonance (MR) imaging as MR imaging offers excellent target identification and allows for continuous monitoring of FUS induced temperature changes. As the dimensions of the ultrasound (US) focus are typically much smaller than the targeted volume, multiple sonications and focus repositioning are interleaved to scan the focus over the target volume. Focal scanning can be achieved electronically by using phased-array US transducers or mechanically by using dedicated mechanical actuators. In this study, the authors propose and evaluate the precision of a combined robotic FUS setup to overcome some of the limitations of the existing MRgFUS systems. Such systems are typically integrated into the patient table of the MR scanner and thus only provide an application of the US wave within a limited spatial range from below the patient. METHODS: The fully MR-compatible robotic assistance system InnoMotion (InnoMedic GmbH, Herxheim, Germany) was originally designed for MR-guided interventions with needles. It offers five pneumatically driven degrees of freedom and can be moved over a wide range within the bore of the magnet. In this work, the robotic system was combined with a fixed-focus US transducer (frequency: 1.7 MHz; focal length: 68 mm, and numerical aperture: 0.44) that was integrated into a dedicated, in-house developed treatment unit for FUS application. A series of MR-guided focal scanning procedures was performed in a polyacrylamide-egg white gel phantom to assess the positioning accuracy of the combined FUS setup. In animal experiments with a 3-month-old domestic pig, the system's potential and suitability for MRgFUS was tested. RESULTS: In phantom experiments, a total targeting precision of about 3 mm was found, which is comparable to that of the existing MRgFUS systems. Focus positioning could be performed within a few seconds. During in vivo experiments, a defined pattern of single thermal lesions and a therapeutically relevant confluent thermal lesion could be created. The creation of local tissue necrosis by coagulation was confirmed by post-FUS MR imaging and histological examinations on the treated tissue sample. During all sonications in phantom and in vivo, reliable MR imaging and online MR thermometry could be performed without compromises due to operation of the combined robotic FUS setup. CONCLUSIONS: Compared to the existing MRgFUS systems, the combined robotic FUS approach offers a wide range of spatial flexibility so that highly flexible application of the US wave would be possible, for example, to avoid risk structures within the US field. The setup might help to realize new ways of patient access in MRgFUS therapy. The setup is compatible with any closed-bore MR system and does not require an especially designed patient table.

Reorganization of gap junctions after focused ultrasound blood-brain barrier opening in the rat brain.

Ultrasound-induced opening of the blood-brain barrier (BBB) is an emerging technique for targeted drug delivery to the central nervous system. Gap junctions allow transfer of information between adjacent cells and are responsible for tissue homeostasis. We examined the effect of ultrasound-induced BBB opening on the structure of gap junctions in cortical neurons, expressing Connexin 36, and astrocytes, expressing Connexin 43, after focused 1-MHz ultrasound exposure at 1.25 MPa of one hemisphere together with intravenous microbubble (Optison, Oslo, Norway) application. Quantification of immunofluorescence signals revealed that, compared with non-insonicated hemispheres, small-sized Connexin 43 and 36 gap-junctional plaques were markedly reduced in areas with BBB breakdown after 3 to 6 hours (34.02+/-6.04% versus 66.49+/-2.16%, P=0.02 for Connexin 43; 33.80+/-1.24% versus 36.77+/-3.43%, P=0.07 for Connexin 36). Complementing this finding, we found significant increases in large-sized gap-junctional plaques (5.76+/-0.96% versus 1.02+/-0.84%, P=0.05 for Connexin 43; 5.62+/-0.22% versus 4.65+/-0.80%, P=0.02 for Connexin 36). This effect was reversible at 24 hours after ultrasound exposure. Western blot analyses did not show any change in the total connexin amount. These results indicate that ultrasound-induced BBB opening leads to a reorganization of gap-junctional plaques in both neurons and astrocytes. The plaque-size increase may be a cellular response to imbalances in extracellular homeostasis after BBB leakage.

Magnetic resonance imaging as a technique for assessing noninvasive tissue ablation using high-intensity ultrasound: an experimental study.

BACKGROUND AND PURPOSE: As a form of noninvasive extracorporeal application, acoustic energy offers an alternative to nephron-sparing surgery for renal masses smaller than 4 cm. The availability of a reliable tool for monitoring the therapy is a prerequisite for safe and successful high-intensity focused ultrasound (HIFU) application. The aim of this study was to evaluate the morphologic visualization of HIFU lesions using MRI. MATERIALS AND METHODS: We used the ex vivo model of the isolated perfused porcine kidney. Treatment was performed using an experimental HIFU system. Complex lesions were induced in 10 kidneys. MRI was performed under constant perfusion of the kidneys. To determine the exact lesion size, we performed a fat-saturated, T1-weighted, volumetric interpolated breath-hold MRI sequence. For perfusion imaging, we used a three-dimensional fast low-angle shot sequence. Subsequently, the lesions were evaluated macroscopically. The width of the complex lesions was defined as x, the length as y, and the depth as z. RESULTS: The MRI scans showed good soft tissue contrast in all sequences. The mean difference for the width of the lesions was 0.2 +/- 1.1 mm; for lesion length and depth, it was 1.7 +/- 1.8 mm and 1.1 +/- 1.3 mm for lesion width, respectively. Statistical evaluation of the x values showed no significant difference between the macroscopic and the MRI data (P = 0.85). The y and z values, however, showed a statistically significant difference (P = 0.071). CONCLUSION: MRI could be a diagnostic tool for monitoring HIFU. Before this modality can be used under clinical conditions, further technical development is indispensable, especially with respect to reducing the measuring times.

[STEAM-sequence with multi-echo-readout for static magnetic resonance elastography]. / STEAM-sequenz mit Multi-Echo-Auslese für die statische Magnetresonanz-Elastographie.

In static magnetic resonance elastography, the elasticity of an object is determined by measuring the internal displacement between two compression states. To reduce signal loss during the long time delay between application of external deformation and the static compression state, a STEAM sequence with a long mixing time is used This results in long scan times. The aim of this work was the development of a STEAM sequence with a multi-echo-readout, which allows the reduction of scan time and number of necessary external deformations. This new sequence was compared to the standard STEAM sequence on an agarose gel phantom with a hard inclusion. In addition, the elasticity of thermal tissue lesions was investigated, which were induced using high-intensity focused ultrasound (HIFU). During a given measurement time, more acquisitions per image can be taken using the multi-echo-readout. As a result the signal-to-noise ratio is increased and errors in the data become clearly smaller. Drawbacks of. the new sequence are its higher signal loss due to T2-decay and its greater sensitivity against ghosting artefacts caused by k-space segmentation. During the investigation of the thermally-induced lesions, a clear contrast in elasticity between normal tissue and the treated region was observed. Taking advantage of the greater accuracy of the new STEAM sequence, it was shown, that this contrast is significantly larger than the one in conventional MR parameters.

Thermal properties and changes of acoustic parameters in an egg white phantom during heating and coagulation by high intensity focused ultrasound.

A polyacrylamide phantom containing egg white has been proposed previously as an adequate tissue-mimicking material for high intensity focused ultrasound (HIFU) application. In this work, we report on measurements of egg white phantom thermal conductivity and specific heat capacity. We measured changes in acoustical properties which occurred during the heating and the coagulation process. Using a thin thermocouple embedded in the phantom material, we recorded the temperature response in the focus of the ultrasound field during HIFU application and phantom coagulation. The measured values for the thermal conductivity (0.59 +/- 0.06 W/m/ degrees C) and the specific heat capacity (4270 +/- 365 J/kg/ degrees C) are similar to the values of water. The attenuation coefficient decreased in the temperature range between 26 degrees C and 50 degrees C and showed a nonlinear dependence on frequency with an exponent of 1.50 +/- 0.05 that was temperature-independent within the investigated temperature range. Below 65 degrees C, no irreversible changes in material absorption were observed. The coagulation process started at 67 degrees C and no adjacent rapid changes in temperature response were detected. In comparison with the noncoagulated phantom, the coagulated phantom material showed an enhanced absorption and a threefold higher attenuation coefficient at a frequency of 1 MHz.

Ablation of clinically relevant kidney tissue volumes by high-intensity focused ultrasound: Preliminary results of standardized ex-vivo investigations.

PURPOSE: To investigate strategies to achieve confluent kidney-tissue ablation by high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Our model of the perfused ex-vivo porcine kidney was used. Tissue ablation was performed with an experimental HIFU device (Storz Medical, Kreuzlingen, Switzerland). Lesion-to-lesion interaction was investigated by varying the lesion distance (5 to 2.5 mm), generator power (300, 280, and 260 W), cooling time (10, 20, and 30 seconds), and exposure time (4, 3, and 2 seconds). The lesion rows were analyzed grossly and by histologic examination (hematoxylin-eosin and nicotinamide adenine dinucleotide staining). RESULTS: It was possible to achieve complete homogeneous ablation of a clinically relevant tissue volume but only by meticulous adjustment of the exposure parameters. Minimal changes in these parameters caused changes in lesion formation with holes within the lesions and lesion-to-lesion interaction. CONCLUSIONS: Our preliminary results show that when using this new device, HIFU can ablate a large tissue volume homogeneously in perfused ex-vivo porcine tissue under standardized conditions with meticulous adjustment of exposure parameters. Further investigations in vivo are necessary to test whether large tissue volumes can be ablated completely and reliably despite the influence of physiologic tissue and organ movement.

Magnetic resonance imaging for assessment of radiofrequency lesions in kidney tissue immediately after ablation: an experimental study.

BACKGROUND AND PURPOSE: Radiofrequency ablation (RFA) is an attractive minimally invasive treatment option for small renal masses. The purpose of this study was to investigate the morphologic imaging appearance of RF lesions immediately after the ablation of kidney tissue using standard clinical MR sequences, as well as to investigate the correlation between MR and gross lesion size. MATERIALS AND METHODS: Ablations were performed 17 times in a standardized model of ex-vivo perfused porcine kidneys using a resistance-controlled RF device (250 W, 470 kHz) and a nonexpandable bipolar applicator inserted into the center of healthy renal parenchyma. The RF current was applied for 9 minutes at 20 W. Imaging was performed after ablation using standard clinical MR sequences: morphologic T(1)/T(2)- weighted images and an isotropic post-contrast T(1) high-resolution measurement (VIBE). Maximum lesion diameters were measured in three directions and were compared with the measurements of the gross lesions. Histologic (hematoxylin + eosin and nicotinamide adenine dinucleotide staining) and statistical analyses were performed. RESULTS: The gross pathologic examination showed a firm, white-yellow ablation zone sharply demarcated from the untreated tissue. The histologic examination confirmed cellular viability outside but not in the treatment zone. The RF lesions were hyperintense on T(1)-weighted images and hypointense on T(2)-weighted images. The lesion size measured in the VIBE images correlated best with the macroscopic lesion size (N = 16). CONCLUSIONS: Morphologic MR T(1) and T(2) sequences of RF lesions immediately after ablation produce reliable and consistent imaging characteristics. The post-contrast, high-resolution sequence (VIBE) enables the extent of the lesion to be determined accurately. The potential uses of this imaging strategy in clinical practise warrant further investigation on human renal-cell carcinoma.

Delivery of substances and their target-specific topical activation.

Goal in pharmaceutical research is achievement of necessary drug concentrations in the target organ, effective treatment with safe delivery of genetic agents, while sparing normal tissue and minimizing side effects. A new "BioShuttle"-delivery system harbouring a cathepsin B cutting site, a nuclear address sequence and a functional peptide was developed and tumor cells were treated. Transport and subcellular activation were determined by confocal laser scanning microscopy permitting the conclusion: BioShuttle-conjugates prove as efficient tools for genetic interventions by selective and topical activation of therapeutic peptide precursors by enzymatic cleavage. As shown here for glioma cells and the cathepsin B cleavable site, living cells can be treated with high specificity and selectivity for diagnostic and therapeutic purposes.

[Comparison of noninvasive MRT procedures for temperature measuremnt for the application of medical heat therapies]. / Vergleich nichtinvasiver MRT-Verfahren zur Temperaturmessung für den Einsatz bei medizinischen Thermotherapien.

Novel methods for hyperthermia tumor therapy, such as high-intensity focused ultrasound (HIFU) or laser-induced thermotherapy (LITT), require accurate non-invasive temperature monitoring. Non-invasive temperature measurement using magnetic resonance imaging (MRI) is based on the analysis of changes in longitudinal relaxation time (T1), diffusion coefficient (D), or water proton resonance frequency (PRF). The purpose of this study was the development and comparative analysis of the three different approaches of MRI temperature monitoring (T1, D, and PRF). Measurements in phantoms (e.g., ultrasound gel) resulted in the following percent changes: T1-relaxation time: 1.98%/degree C; diffusion coefficient: 2.22%/degree C; and PRF: -0.0101 ppm/degree C. All measurements were in good agreement with the literature. Temperature resolutions could also be measured from the inverse correlation of the data over the whole calibration range: T1: 2.1 +/- 0.6 degrees C; D: 0.93 +/- 0.2 degree C; and PRF: 1.4 +/- 0.3 degrees C. The diffusion and PRF methods were not applicable in fatty tissue. The use of the diffusion method was restricted due to prolonged echo time and anisotropic diffusion in tissue. Initial tests with rabbit muscle tissue in vivo indicated that MR thermometry via T1 and PRF procedures is feasible to monitor the local heating process induced by HIFU. The ultrasound applicators in the MR scanner did not substantially interfere with image quality.

[MRI-guided surgery with high intensity focused ultrasound]. / MRT-überwachte Chirurgie mit hochenergetischem fokussiertem Ultraschall.

High-intensity focused ultrasound allows high-precision, non-invasive thermocoagulation of tissues within seconds, with sparing of surrounding areas. The resulting tissue necrosis is so sharply demarcated that the technique is also defined focused ultrasound surgery (FUS). The combination with magnetic resonance imaging (MRI) allows an exact definition of the target volume and a safe guidance of FUS. The present paper describes the physical equipment necessary to perform MRI-guided FUS, and reports an example of application of this technique for the therapy of breast cancer. Finally, the paper outlines further examples of FUS application and future perspectives.