Quantification of near-field heating during volumetric MR-HIFU ablation.

PURPOSE: High-intensity focused ultrasound guided by magnetic resonance imaging has been extensively evaluated during the past decade as a clinical alternative for thermal ablation of tumor tissue. However, the maximal ablation volume is limited by the extensive treatment duration resulting from the small size of the focal point as compared to the average tumor size. Volumetric sonication has been shown to efficiently enlarge the ablated volume per sonication, but remains limited by the temperature increase induced in the skin and fat layers. In this study, multiplane MR thermometry is proposed for monitoring the near-field temperature rise in order to prevent related unintended thermal damage. METHODS: The method was evaluated by performing sonications in the thigh muscle of 11 pigs maintained under general anesthesia. Volumetric ablations were performed by steering the focal point along trajectories consisting of multiple outward-moving concentric circles. Near-field heating was characterized with MR temperature maps and thermal dose maps. The results from the MR measurements were compared to simulations. RESULTS: In this study, the measured maximum temperature rise was found to correlate linearly with the surface energy density within the near field of the beam path with a slope of 4.2 K mm2/J. This simple linear model appears to be almost independent of the trajectory pattern and the sonication depth. The safety limit to avoid lethal damage of the subcutaneous tissues of the porcine thigh was identified to be an absolute temperature of 50 degrees C, corresponding to a surface energy density of 2.5 J/mm2 at 1.2 MHz. CONCLUSIONS: A linear relationship can be established to estimate the temperature increase based on the chosen power prior to ablation, thereby providing an a priori safety check for possible excessive near-field heating using a known surface energy density threshold. This method would also give the clinician the possibility to abort the sonication should excessive near-field temperature rise be seen before fat layer damage or skin burns are inflicted.

Molecular MR imaging and MR-guided ultrasound therapies in cancer.

Imaging in cancer has moved in the last twenty years from morphological detection of diseases to characterization and categorization of different subtypes of tumors. Functional information, based on dynamic contrast-enhanced imaging of tissue perfusion and evaluation of water diffusion, tissue oxygenation, capillary permeability or lymphatic drainage, plays a major role in that field.The next coming steps will concern the differentiation of biological behaviour of tumors according to their phenotypes by identifying specific surface receptors or products of synthesis.These developments allowing an in vivo identification of the tumor biological singularities is a tremendous progress in the management of cancer at the step of diagnosis but, more importantly, to assess the most appropriated treatment to each tumor type. At the same time, minimally invasive methods of treatment of tumors have also developed, mainly in the field of thermotherapies. Ablation of tumors using radiofrequency is now used in clinics as a new standard within the liver and as a promising additional option in many other organs as kidney, lung and bone. High intensity focused ultrasound (HIFU) showed more restricted developments in clinics, mainly applied to prostatic cancer, because of many technical barriers. We believe that magnetic resonance (MR) imaging and MR-guided HIFU (MRgHIFU) have a great potential in that field due to the capacity of MR imaging to monitor temperature changes for an optimal heat deposition and for an optimal safety. This technique has already gained recognition for the treatment of uterine leiomyomas. But it has still to prove its efficacy in treatment of malignant tumors. This review will focus on some recent developments in molecular characterisation of tumors using MR imaging and in technical improvements necessary for accurate application of MRgHIFU in cancer.

[Therapies by focused ultrasound]. / Thérapies par ultrasons focalisés.

Many techniques of thermotherapy have emerged over the last several years in the field of oncology using different types of physical agents, including ultrasound. Only ultrasound can target deep seated lesions non-invasively without need for percutaneous probe insertion. Depending on their utilization, it is possible to select either thermal effects, in a continuous mode, at low temperature (allowing thermo-induced biological effects) or at high temperature (allowing thermoablation), or mechanical effects, in a pulsed mode, at low energy level (allowing biological effects) or at high energy levels (histotripsy). Thermoablation by focused ultrasound is now developing fast for applications in many organs. It gained a well defined role for the treatment of prostatic cancer and uterine leiomyoma but needs to be better evaluated in other organs such as the breast. Treatment of abdominal tumors must still be considered as experimental as long as problems related to acoustic interfaces (produced by ribs and gas) and movement correction are not resolved. Biological applications of focused ultrasound are currently being explored and have a great long term potential.

64-element intraluminal ultrasound cylindrical phased array for transesophageal thermal ablation under fast MR temperature mapping: an ex vivo study.

This work was undertaken to investigate the feasibility of using a cylindrical phased array for transoesophaeal thermal ablation under magnetic resonance (MR) imaging guidance. Sixty-four transducers (0.45 mm wide by 15 mm tall), operating at 4.6 MHz, were spread around the periphery of a 10.6-mm-diam cylinder. The head of the applicator was covered with a 65-microm thick latex balloon attached using watertight seals. This envelope was inflated with degassed water to provide acoustic coupling between the transducer and the tissues. The underlying operating principle of this applicator is to rotate a plane ultrasound beam electronically. For this purpose, eight adjacent transducers were excited with appropriate delay times so as to generate a plane wave. The exposure direction was changed by exciting a different set of eight elements. Ex vivo experiments conducted on 47 samples of pig liver under MR temperature monitoring demonstrated the ability of this applicator to generate cylindrical or sector-based coagulation necroses at depths up to 19 mm with excellent angular precision by applying 20 W/cm2. MR thermometry was performed in "real-time" with segmented echo-planar imaging gradient echo sequences. The temporal resolution was approximately 3 s/ image. The average value for the temperature baseline in liver tissue close to the applicator was 0.3 degrees C (+/- 0.6 degrees C). The thermal dose delivered in tissues was computed on-line during temperature imaging. Excellent MR compatibility was demonstrated, all MR acquisitions were performed without susceptibility artifacts or radio-frequency interferences with the ultrasound device. Thermal lesions identified on post-treatment follow up showed good correlation with online MR thermometry data. The individual differences between measurements performed visually and using MRI thermal dose maps were about 11% of volume. This study demonstrated the feasibility of thermal ablation using a phased array intraluminal ultrasound applicator and on-line MR monitoring.

Magnetic resonance temperature imaging.

Continuous, real-time, 3D temperature mapping during a hyperthermic procedure may provide (i) enhanced safety by visualizing temperature maps in and around the treated region, (ii) improved efficiency by adapting local energy deposition with feedback coupling algorithms and (iii) therapy end-points based on the accumulated thermal dose. Non-invasive mapping of temperature changes can be achieved with MRI and may be based on temperature dependent MRI parameters. The excellent linearity of the temperature dependency of the proton resonance frequency (PRF) and its near-independence with respect to tissue type make the PRF-based methods the preferred choice for many applications, in particular at mid- to-high field strength (> or =0.5 T). The PRF methods employ RF-spoiled gradient echo imaging methods and incorporate fat suppression techniques for most organs. A standard deviation of less than 1 degrees C, for a temporal resolution below 1 s and a spatial resolution of approximately 2 mm is feasible for immobile tissues. Special attention is paid to methods for reducing artifacts in MR temperature mapping caused by intra-scan and inter-scan motion and motion and temperature-induced susceptibility effects in mobile tissues. Real-time image processing and visualization techniques, together with accelerated MRI acquisition techniques, are described because of their potential for therapy guidance.

Spatial and temporal control of transgene expression in vivo using a heat-sensitive promoter and MRI-guided focused ultrasound.

BACKGROUND: Among the techniques used to induce and control gene expression, a non-invasive, physical approach based on local heat in combination with a heat-sensitive promoter represents a promising alternative but requires accurate temperature control in vivo. MRI-guided focused ultrasound (MRI-FUS) with real-time feedback control allows automatic execution of a predefined temperature-time trajectory. The purpose of this study was to demonstrate temporal and spatial control of transgene expression based on a well-defined local hyperthermia generated by MRI-FUS. METHODS: Expression of the green fluorescent protein (GFP) marker gene was used. Two cell lines were derived from C6 glioma cells. The GFP expression of the first one is under the control of the CMV promoter, whereas it is under the control of the HSP70 promoter in the second one and thus inducible by heat. Subcutaneous tumours were generated by injection in immuno-deficient mice and rats. Tumours were subjected to temperatures varying from 42 to 50 degrees C for 3 to 25 min controlled by MRI-FUS and analyzed 24 h after the heat-shock. Endogenous HSP70 expression and C6 cell distribution were also analyzed. RESULTS: The results demonstrate strong expression at 50 degrees C applied during a short time period (3 min) without affecting cell viability. Induced expression was also clearly shown for temperature in the range 44-48 degrees C but not at 42 degrees C. CONCLUSIONS: Heating with MRI-FUS allows a tight and non-invasive control of transgene expression in a tumour.

On-line correction and visualization of motion during MRI-controlled hyperthermia.

Displacement of tissue during MRI-controlled hyperthermia therapy can cause significant problems. Errors in calculated temperature may result from motion-related image artifacts and inter-image object displacement, leading to incorrect spatial temperature reference. Here, cyclic navigator echoes were incorporated in rapid gradient-echo MRI sequences, used for temperature mapping based on the proton resonance frequency. On-line evaluation of navigator information was used in three ways. First, motion artifacts were minimized in echo-shifted (TE > TR) gradient-echo images using the phase information of the navigator echo. Second, navigator profiles were matched for a quantitative evaluation of displacement. Together with a novel processing method, this information was employed to correct the reference temperature maps, thereby avoiding persistence of motion-related temperature errors throughout the hyperthermic period. Third, on-line visualization of displacement, together with temperature maps and thermal dose images, was developed, allowing physician intervention at all times. Examples are given of on-line corrections during hyperthermia procedures with focused ultrasound and radiofrequency heat sources. Magn Reson Med 45:128-137, 2001.

Thermal therapies in interventional MR imaging. Focused ultrasound.

MR image-guided focused ultrasound (FUS) provides an entirely noninvasive approach for local thermal therapies. MR imaging allows target definition and continuous temperature mapping. Therefore, the heating procedure can be controlled spatially and temporally based on automatic feedback to the FUS apparatus. Phased-array ultrasound technology will further help the development. MR imaging/FUS may be applied not only for tissue ablation, but also for local drug delivery, gene therapy, and drug activation.

Magnetic resonance temperature imaging for guidance of thermotherapy.

Continuous thermometry during a hyperthermic procedure may help to correct for local differences in heat conduction and energy absorption, and thus allow optimization of the thermal therapy. Noninvasive, three-dimensional mapping of temperature changes is feasible with magnetic resonance (MR) and may be based on the relaxation time T(1), the diffusion coefficient (D), or proton resonance frequency (PRF) of tissue water. The use of temperature-sensitive contrast agents and proton spectroscopic imaging can provide absolute temperature measurements. The principles and performance of these methods are reviewed in this paper. The excellent linearity and near-independence with respect to tissue type, together with good temperature sensitivity, make PRF-based temperature MRI the preferred choice for many applications at mid to high field strength (>/= 1 T). The PRF methods employ radiofrequency spoiled gradient-echo imaging methods. A standard deviation of less than 1 degrees C, for a temporal resolution below 1 second and a spatial resolution of about 2 mm, is feasible for a single slice for immobile tissues. Corrections should be made for temperature-induced susceptibility effects in the PRF method. If spin-echo methods are preferred, for example when field homogeneity is poor due to small ferromagnetic parts in the needle, the D- and T(1)-based methods may give better results. The sensitivity of the D method is higher that that of the T(1) methods provided that motion artifacts are avoided and the trace of D is evaluated. Fat suppression is necessary for most tissues when T(1), D, or PRF methods are employed. The latter three methods require excellent registration to correct for displacements between scans.

Local hyperthermia with MR-guided focused ultrasound: spiral trajectory of the focal point optimized for temperature uniformity in the target region.

The objective of hyperthermia treatment is to deliver a similar therapeutic thermal dose throughout the target volume within a minimum amount of time. We describe a noninvasive approach to this goal based on magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) with a spherical transducer that can be moved along two directions inside the bed of a clinical MR imager and that has an adjustable focal length in the third dimension. Absorption of FUS gives rise to a highly localized thermal buildup, which then spreads by heat diffusion and blood perfusion. A uniform temperature within a large target volume can be obtained using a double spiral trajectory of the transducer focal point together with constant and maximum FUS power. Differences between the real and target temperatures during the first spiral are evaluated in real time with temperature MRI and corrected for during the second spiral trajectory employing FUS focal point velocity modulation. Once a uniform temperature distribution is reached within the entire volume, FUS heating is applied only at the region's boundaries to maintain the raised temperature levels. Heat conduction, together with the design and timing of the trajectories, therefore ensures a similar thermal dose for the entire target region. Good agreement is obtained between theory and experimental results in vitro on gel phantoms, ex vivo on meat samples, and in vivo on rabbit thigh muscle. Edema in muscle was visible 1 hour after hyperthermia as a spatially uniform rise of the signal intensity in T(2)-weighted images.

Hyperthermia by MR-guided focused ultrasound: accurate temperature control based on fast MRI and a physical model of local energy deposition and heat conduction.

Temperature regulation in MR-guided focused ultrasound requires rapid MR temperature mapping and automatic feedback control of the ultrasound output. Here, a regulation method is proposed based on a physical model of local energy deposition and heat conduction. The real-time evaluation of local temperature gradients from temperature maps is an essential element of the control system. Each time a new image is available, ultrasound power is adjusted on-the-fly in order to obtain the desired evolution of the focal point temperature. In vitro and in vivo performance indicated fast and accurate control of temperature and a large tolerance of errors in initial estimates of ultrasound absorption and heat conduction. When using correct estimates for the physical parameters of the model, focal point temperature was controlled within the measurement noise limit. Initial errors in absorption and diffusion parameters are compensated for exponentially with a user-defined response time, which is suggested to be on the order of 10 sec.

Real-time control of focused ultrasound heating based on rapid MR thermometry.

RATIONALE AND OBJECTIVES: Real-time control of the heating procedure is essential for hyperthermia applications of focused ultrasound (FUS). The objective of this study is to demonstrate the feasibility of MRI-controlled FUS. METHODS: An automatic control system was developed using a dedicated interface between the MR system control computer and the FUS wave generator. Two algorithms were used to regulate FUS power to maintain the focal point temperature at a desired level. RESULTS: Automatic control of FUS power level was demonstrated ex vivo at three target temperature levels (increase of 5 degrees C, 10 degrees C, and 30 degrees C above room temperature) during 30-minute hyperthermic periods. Preliminary in vivo results on rat leg muscle confirm that necrosis estimate, calculated on-line during FUS sonication, allows prediction of tissue damage. CONCLUSIONS. The feasibility of fully automatic FUS control based on MRI thermometry has been demonstrated.

In vivo NMR diffusion spectroscopy: 31P application to phosphorus metabolites in muscle.

Apparent diffusion coefficients (Da) of individual metabolites can be studied in vivo by diffusion NMR spectroscopy using an echo sequence sensitized to molecular motion. The methods are based on the echo attenuation due to phase dispersion resulting from incoherent displacement during the diffusion time. As the displacement of metabolites by diffusion in vivo can be affected by compartment size, temperature, adsorption processes, etc., the presented methods are potentially useful in studying such phenomena in vivo. Here, the methods are applied to phosphocreatine in the rat quadriceps muscle. It is demonstrated that the displacement of phosphocreatine resembles free diffusion for short diffusion times but becomes limited as a result of boundaries due to compartmentation for longer diffusion times. The limit of the displacement indicates an apparent average size of 44 microns of the compartment in the direction of the diffusion gradient. As the gradient was applied approximately parallel (angle less than 25 degrees) to the muscle fiber, this result indicates that phosphocreatine moves freely in the cytosol but is limited by the boundaries of the muscle cells. Error analyses are performed with regard to motion artifacts and gradient performance. The methods were tested extensively for distilled water and free metabolites.

31P spectroscopy in thrombolytic treatment of experimental cerebral infarct.

Ischemic changes produced by autogenous clot embolization of intracranial arteries were monitored by continuous surface-coil 31P spectroscopy in 12 rabbits: six were used as controls and six were treated intravenously with tissue-type plasminogen activator. The animals were sacrificed and the brains were fixed with intravital stains. The results indicate that spectral changes are reversible only when thrombolysis therapy is started within 30 min after ischemic changes are detected. The improvement of the 31P spectrum correlated with postmortem changes.

A comparative carbon-13, nitrogen-15, and phosphorus-31 nuclear magnetic resonance study on the flavodoxins from Clostridium MP, Megasphaera elsdenii, and Azotobacter vinelandii.

The flavodoxins from Megasphaera elsdenii, Clostridium MP, and Azotobacter vinelandii were studied by 13C, 15N, and 31P NMR techniques by using various selectivity enriched oxidized riboflavin 5'-phosphate (FMN) derivatives. It is shown that the pi electron distribution in protein-bound flavin differs from that of free flavin and depends also on the apoflavoprotein used. In the oxidized state Clostridium MP and M. elsdenii flavodoxins are very similar with respect to specific hydrogen bond interaction between FMN and the apoprotein and the electronic structure of flavin. A. vinelandii flavodoxin differs from these flavodoxins in both respects, but it also differs from Desulfovibrio vulgaris flavodoxin. The similarities between A. vinelandii and D. vulgaris flavodoxins are greater than the similarities with the other two flavodoxins. The differences in the pi electron distribution in the FMN of reduced flavodoxins from A. vinelandii and D. vulgaris are even greater, but the hydrogen bond patterns between the reduced flavins and the apoflavodoxins are very similar. In the reduced state all flavodoxins studied contain an ionized prosthetic group and the isoalloxazine ring is in a planar conformation. The results are compared with existing three-dimensional data and discussed with respect to the various possible mesomeric structures in protein-bound FMN. The results are also discussed in light of the proposed hypothesis that specific hydrogen bonding to the protein-bound flavin determines the specific biological activity of a particular flavoprotein.