Deep correction of breathing-related artifacts in real-time MR-thermometry.

Real-time MR-imaging has been clinically adapted for monitoring thermal therapies since it can provide on-the-fly temperature maps simultaneously with anatomical information. However, proton resonance frequency based thermometry of moving targets remains challenging since temperature artifacts are induced by the respiratory as well as physiological motion. If left uncorrected, these artifacts lead to severe errors in temperature estimates and impair therapy guidance. In this study, we evaluated deep learning for on-line correction of motion related errors in abdominal MR-thermometry. For this, a convolutional neural network (CNN) was designed to learn the apparent temperature perturbation from images acquired during a preparative learning stage prior to hyperthermia. The input of the designed CNN is the most recent magnitude image and no surrogate of motion is needed. During the subsequent hyperthermia procedure, the recent magnitude image is used as an input for the CNN-model in order to generate an on-line correction for the current temperature map. The method's artifact suppression performance was evaluated on 12 free breathing volunteers and was found robust and artifact-free in all examined cases. Furthermore, thermometric precision and accuracy was assessed for in vivo ablation using high intensity focused ultrasound. All calculations involved at the different stages of the proposed workflow were designed to be compatible with the clinical time constraints of a therapeutic procedure.

Assessment of 3D motion modeling performance for dose accumulation mapping on the MR-linac by simultaneous multislice MRI.

Hybrid MR-linac systems enable intrafraction motion monitoring during radiation therapy. Since time-resolved 3D MRI is still challenging, various motion models have been developed that rely on time-resolved 2D imaging. Continuous validation of these models is important for accurate dose accumulation mapping. In this study we used 2D simultaneous multislice (SMS) imaging to improve the PCA-based motion modeling method developed previously (Stemkens et al 2016 Phys. Med. Biol. 61 5335-55). From the additional simultaneously acquired slices, several independent motion models could be generated, which allowed for an assessment of the sensitivity of the motion model to the location of the time-resolved 2D slices. Additionally, the best model could be chosen at every time-point, increasing the method's robustness. Imaging experiments were performed in six healthy volunteers using three simultaneous slices, which generated three independent models per volunteer. For each model the motion traces of the liver tip and both kidneys were estimated. We found that the location of the 2D slices influenced the model's error in five volunteers significantly with a p -value <0.05, and that selecting the best model at every time-point can improve the method. This allows for more accurate and robust motion characterization in MR-guided radiotherapy.

Anatomically plausible models and quality assurance criteria for online mono- and multi-modal medical image registration.

Medical imaging is currently employed in the diagnosis, planning, delivery and response monitoring of cancer treatments. Due to physiological motion and/or treatment response, the shape and location of the pathology and organs-at-risk may change over time. Establishing their location within the acquired images is therefore paramount for an accurate treatment delivery and monitoring. A feasible solution for tracking anatomical changes during an image-guided cancer treatment is provided by image registration algorithms. Such methods are, however, often built upon elements originating from the computer vision/graphics domain. Since the original design of such elements did not take into consideration the material properties of particular biological tissues, the anatomical plausibility of the estimated deformations may not be guaranteed. In the current work we adapt two existing variational registration algorithms, namely Horn-Schunck and EVolution, to online soft tissue tracking. This is achieved by enforcing an incompressibility constraint on the estimated deformations during the registration process. The existing and the modified registration methods were comparatively tested against several quality assurance criteria on abdominal in vivo MR and CT data. These criteria included: the Dice similarity coefficient (DSC), the Jaccard index, the target registration error (TRE) and three additional criteria evaluating the anatomical plausibility of the estimated deformations. Results demonstrated that both the original and the modified registration methods have similar registration capabilities in high-contrast areas, with DSC and Jaccard index values predominantly in the 0.8-0.9 range and an average TRE of 1.6-2.0 mm. In contrast-devoid regions of the liver and kidneys, however, the three additional quality assurance criteria have indicated a considerable improvement of the anatomical plausibility of the deformations estimated by the incompressibility-constrained methods. Moreover, the proposed registration models maintain the potential of the original methods for online image-based guidance of cancer treatments.

Characterization of imaging latency for real-time MRI-guided radiotherapy.

Hybrid MR-linac systems can use fast dynamic MR sequences for tumor tracking and adapt the radiation treatment in real-time. For this the imaging latency must be as short as possible. This work describes how different acquisition parameters influence this latency. First, the latency was measured for Cartesian readouts with phase encode orderings linear, reverse-linear, and high-low. Second, the latency was measured for radial readouts with linear and golden angle profile orderings. To reduce the latency, a spatio-temporal (k-t) filter that suppresses the k-space center of earlier acquired spokes was implemented for the golden angle sequence. For Cartesian readouts a high-low ordering achieved a three times lower latency compared to a linear ordering with our sampling parameters. For radial readouts the filter was able to reduce the acquisition latency from half the acquisition time to a quarter of the acquisition time. The filter did not compromise the signal-to-noise ratio and the artifact power.

Real-time non-rigid target tracking for ultrasound-guided clinical interventions.

Biological motion is a problem for non- or mini-invasive interventions when conducted in mobile/deformable organs due to the targeted pathology moving/deforming with the organ. This may lead to high miss rates and/or incomplete treatment of the pathology. Therefore, real-time tracking of the target anatomy during the intervention would be beneficial for such applications. Since the aforementioned interventions are often conducted under B-mode ultrasound (US) guidance, target tracking can be achieved via image registration, by comparing the acquired US images to a separate image established as positional reference. However, such US images are intrinsically altered by speckle noise, introducing incoherent gray-level intensity variations. This may prove problematic for existing intensity-based registration methods. In the current study we address US-based target tracking by employing the recently proposed EVolution registration algorithm. The method is, by construction, robust to transient gray-level intensities. Instead of directly matching image intensities, EVolution aligns similar contrast patterns in the images. Moreover, the displacement is computed by evaluating a matching criterion for image sub-regions rather than on a point-by-point basis, which typically provides more robust motion estimates. However, unlike similar previously published approaches, which assume rigid displacements in the image sub-regions, the EVolution algorithm integrates the matching criterion in a global functional, allowing the estimation of an elastic dense deformation. The approach was validated for soft tissue tracking under free-breathing conditions on the abdomen of seven healthy volunteers. Contact echography was performed on all volunteers, while three of the volunteers also underwent standoff echography. Each of the two modalities is predominantly specific to a particular type of non- or mini-invasive clinical intervention. The method demonstrated on average an accuracy of ∼1.5 mm and submillimeter precision. This, together with a computational performance of 20 images per second make the proposed method an attractive solution for real-time target tracking during US-guided clinical interventions.

Evaluation of a novel therapeutic focused ultrasound transducer based on Fermat's spiral.

The purpose of this study was to evaluate a novel phased array transducer design rule for therapeutic focused ultrasound applications. This design rule uses the discretized Fermat's spiral to determine the positioning of the transducer elements for a given number of elements and f-number. Using this principle, three variations of Fermat's spiral were generated, aimed at (1) grating lobe minimization, (2) side lobe minimization, and (3) an optimized element packing efficiency. For each spiral, sparse layouts using identical circular elements and fully populated layouts based on additional Voronoi tessellation were evaluated numerically. Evaluation criteria included the element size distribution, beam steering capabilities, focal plane pressure distribution, prefocal pressure distribution, and practical considerations. Finally, one Voronoi-tessellated design with a focal length and aperture diameter of 16 cm and a natural frequency of 1.3 MHz was evaluated experimentally through hydrophone measurements. The numerical evaluation showed that while sparse arrays possess superior beam steering capabilities for a given number of elements, the focal point quality and prefocal pressure distribution is substantially more favorable when using the Voronoi-tessellated designs. Beam steering was shown to be feasible with the tessellated designs for lateral deflections up to 10 mm and axial deflections up to 20 mm. The experimental evaluation showed that such a transducer is capable of inducing 40.00 MPa rarefactional and 237.50 MPa compressional peak pressure levels at 800 W instantaneous acoustic output power under free-field conditions, making the system potentially relevant for thermal ablation therapy, histotripsy applications, and shockwave-enhanced heating.

Thermal ablation of a confluent lesion in the porcine kidney with a clinically available MR-HIFU system.

The incidence of small renal masses (SRMs) sized <4 cm has increased over the decades (as co-findings/or due to introduction of cross sectional imaging). Currently, partial nephrectomy (PN) or watchful waiting is advised in these patients. Ultimately, 80-90% of these SRMs require surgical treatment and PN is associated with a 15% complication rate. In this aging population, with possible comorbidities and poor health condition, both PN and watchful waiting are non-ideal treatment options. This resulted in an increased need for early, non-invasive treatment strategies such as MR-guided high intensity focused ultrasound (MR-HIFU). (i) To investigate the feasibility of creating a confluent lesion in the kidney using respiratory-gated MR-HIFU under clinical conditions in a pre-clinical study and (ii) to evaluate the reproducibility of the MR-HIFU ablation strategy. Healthy pigs (n = 10) under general anesthesia were positioned on a clinical MR-HIFU system with integrated cooling. A honeycomb pattern of seven overlapping ablation cells (4 × 4 × 10 mm3, 450 W, <30 s) was ablated successively in the cortex of the porcine kidney. Both MR thermometry and acoustic energy delivery were respiratory gated using a pencil beam navigator on the contralateral kidney. The non-perfused volume (NPV) was visualized after the last sonication by contrast-enhanced (CE) T 1-weighted MR (T 1 w) imaging. Cell viability staining was performed to visualize the extent of necrosis. RESULTS: a median NPV of 0.62 ml was observed on CE-T 1 w images (IQR 0.58-1.57 ml, range 0.33-2.75 ml). Cell viability staining showed a median damaged volume of 0.59 ml (IQR 0.24-1.35 ml, range 0-4.1 ml). Overlooking of the false rib, shivering of the pig, and too large depth combined with a large heat-sink effect resulted in insufficient heating in 4 cases. The NPV and necrosed volume were confluent in all cases in which an ablated volume could be observed. Our results demonstrated the feasibility of creating a confluent volume of ablated kidney cortical tissue in vivo with MR-HIFU on a clinically available system using respiratory gating and near-field cooling and showed its reproducibility.

Dynamic Fluorescence Microscopy of Cellular Uptake of Intercalating Model Drugs by Ultrasound-Activated Microbubbles.

PURPOSE: The combination of ultrasound and microbubbles can facilitate cellular uptake of (model) drugs via transient permeabilization of the cell membrane. By using fluorescent molecules, this process can be studied conveniently with confocal fluorescence microscopy. This study aimed to investigate the relation between cellular uptake and fluorescence intensity increase of intercalating model drugs. PROCEDURES: SYTOX Green, an intercalating fluorescent dye that displays >500-fold fluorescence enhancement upon binding to nucleic acids, was used as a model drug for ultrasound-induced cellular uptake. SYTOX Green uptake was monitored in high spatiotemporal resolution to qualitatively assess the relation between uptake and fluorescence intensity in individual cells. In addition, the kinetics of fluorescence enhancement were studied as a function of experimental parameters, in particular, laser duty cycle (DC), SYTOX Green concentration and cell line. RESULTS: Ultrasound-induced intracellular SYTOX Green uptake resulted in local fluorescence enhancement, spreading throughout the cell and ultimately accumulating in the nucleus during the 9-min acquisition. The temporal evolution of SYTOX Green fluorescence was substantially influenced by laser duty cycle: continuous laser (100 % DC) induced a 6.4-fold higher photobleaching compared to pulsed laser (3.3 % DC), thus overestimating the fluorescence kinetics. A positive correlation of fluorescence kinetics and SYTOX Green concentration was found, increasing from 0.6 × 10-3 to 2.2 × 10-3 s-1 for 1 and 20 µM, respectively. Finally, C6 cells displayed a 2.4-fold higher fluorescence rate constant than FaDu cells. CONCLUSIONS: These data show that the temporal behavior of intracellular SYTOX Green fluorescence enhancement depends substantially on nuclear accumulation and not just on cellular uptake. In addition, it is strongly influenced by the experimental conditions, such as the laser duty cycle, SYTOX Green concentration, and cell line.

Towards real-time thermometry using simultaneous multislice MRI.

MR-guided thermal therapies, such as high-intensity focused ultrasound (MRgHIFU) and laser-induced thermal therapy (MRgLITT) are increasingly being applied in oncology and neurology. MRI is used for guidance since it can measure temperature noninvasively based on the proton resonance frequency shift (PRFS). For therapy guidance using PRFS thermometry, high temporal resolution and large spatial coverage are desirable. We propose to use the parallel imaging technique simultaneous multislice (SMS) in combination with controlled aliasing (CAIPIRINHA) to accelerate the acquisition. We compare this with the sensitivity encoding (SENSE) acceleration technique. Two experiments were performed to validate that SMS can be used to increase the spatial coverage or the temporal resolution. The first was performed in agar gel using LITT heating and a gradient-echo sequence with echo-planar imaging (EPI), and the second was performed in bovine muscle using HIFU heating and a gradient-echo sequence without EPI. In both experiments temperature curves from an unaccelerated scan and from SMS, SENSE, and SENSE/SMS accelerated scans were compared. The precision was quantified by a standard deviation analysis of scans without heating. Both experiments showed a good agreement between the temperature curves obtained from the unaccelerated, and SMS accelerated scans, confirming that accuracy was maintained during SMS acceleration. The standard deviations of the temperature measurements obtained with SMS were significantly smaller than when SENSE was used, implying that SMS allows for higher acceleration. In the LITT and HIFU experiments SMS factors up to 4 and 3 were reached, respectively, with a loss of precision of less than a factor of 3. Based on these results we conclude that SMS acceleration of PRFS thermometry is a valuable addition to SENSE, because it allows for a higher temporal resolution or bigger spatial coverage, with a higher precision.

Increasing the HIFU ablation rate through an MRI-guided sonication strategy using shock waves: feasibility in the in vivo porcine liver.

This study investigated whether an MR-guided pulsed HIFU ablation strategy could be implemented under clinical conditions, using a transducer designed for uterine fibroid ablation, to obtain an ablation rate that is sufficiently high for clinical abdominal HIFU therapy in highly perfused organs. A pulsed HIFU ablation strategy, aimed at increasing the energy absorption in the HIFU focal area by local shock wave formation in the non-linear pressure regime, was compared to an energy-equivalent continuous wave sonication strategy in the linear pressure regime. Both ablation strategies were used for transcutaneous sonication of pre-defined treatment cells in the livers of 5 pigs in vivo. Temperature evolution in both the target area as well as the pre-focal muscle layer was monitored simultaneously using MR thermometry. Local energy absorption and thermal dose volumes were shown to be increased using the pulsed ablation strategy, while preserving healthy tissue in the near field of the acoustic beam. Respiratory motion compensation of both acoustic energy delivery and MR thermometry was applied through gating based on MR navigator echoes. Histopathology showed that confluent vacuolated thermal lesions were created when the pulsed ablation strategy was used. Additionally, it was shown that the heat sink effect caused by the presence of larger vessels could be overcome. The pulsed HIFU ablation strategy achieved an ablation rate of approximately 4 ml per hour in the in vivo porcine liver, without causing undesired damage to healthy tissues in the near field.

Intercostal high intensity focused ultrasound for liver ablation: The influence of beam shaping on sonication efficacy and near-field risks.

PURPOSE: One of the major issues in high intensity focused ultrasound ablation of abdominal lesions is obstruction of the ultrasound beam by the thoracic cage. Beam shaping strategies have been shown by several authors to increase focal point intensity while limiting rib exposure. However, as rib obstruction leaves only part of the aperture available for energy transmission, conserving total emitted acoustic power, the intensity in the near-field tissues inherently increases after beam shaping. Despite of effective rib sparing, those tissues are therefore subjected to increased risk of thermal damage. In this study, for a number of clinically representative intercostal sonication geometries, modeling clinically available hardware, the effect of beam shaping on both the exposure of the ribs and near-field to acoustic energy was evaluated and the implications for the volumetric ablation rate were addressed. METHODS: A relationship between rib temperature rise and acoustic energy density was established by means of in vivo MR thermometry and simulations of the incident acoustic energy for the corresponding anatomies. This relationship was used for interpretation of rib exposure in subsequent numerical simulations in which rib spacing, focal point placement, and the focal point trajectory were varied. The time required to heat a targeted region to 65 °C was determined without and with the application of beam shaping. The required sonication time was used to calculate the acoustic energy density at the fat-muscle interface and at the surface of the ribs. At the fat-muscle interface, exposure was compared to available literature data and rib exposure was interpreted based on the earlier obtained relation between measured temperature rise and simulated acoustic energy density. To estimate the volumetric ablation rate, the cool-down time between periods of energy exposure was estimated using a time-averaged power limit of 100 kJ/h. RESULTS: At the level of the ribs, the temperature rise-energy density proportionality constant was estimated to be 6.0-7.6 °C/(J/mm(2)). Beam shaping by the geometric shadow method typically reduces the acoustic intensity a factor of 2, considering the 1 cm(2) with the highest exposure. For a 4 mm diameter circular sonication trajectory, the near-field energy limit of 2.5 J/mm(2) was exceeded for all considered geometries. The estimated rib temperature was in all but one (sonication 50 mm behind the ribs, with 15 mm rib spacing and a 4 mm diameter circular sonication trajectory) of the considered scenarios within acceptable limits. For those sonication scenarios where a single sonication is considered safe both in terms of near-field as well as rib heating, volumetric ablation rates in the order of 1 ml/h are estimated. CONCLUSIONS: Intercostal sonication is associated with an increased risk of near-field overheating. This risk is strongly dependent on the considered rib spacing, the placement of the focus behind the ribs, and the selected sonication trajectory. For the hardware under simulation, obstruction by the thoracic cage renders ablations of clinically relevant volumes within a practical time-frame unfeasible in a large part of the liver. Improvements maybe expected from transducer designs with a larger active surface and/or nonlinear sonication strategies.

Performance analysis of a dedicated breast MR-HIFU system for tumor ablation in breast cancer patients.

MR-guided HIFU ablation is a promising technique for the non-invasive treatment of breast cancer. A phase I study was performed to assess the safety and treatment accuracy and precision of MR-HIFU ablation in breast cancer patients (n=10) using a newly developed MR-HIFU platform dedicated to applications in the breast. In this paper a technical analysis of the performance of the dedicated breast MR-HIFU system during breast tumors ablation is described. The main points of investigation were the spatial targeting accuracy and precision of the system and the performance of real-time respiration-corrected MR thermometry.The mean targeting accuracy was in the range of 2.4-2.6 mm, whereas the mean targeting precision was in the range of 1.5-1.8 mm. To correct for respiration-induced magnetic field fluctuations during MR temperature mapping a look-up-table (LUT)-based correction method was used. An optimized procedural sedation protocol in combination with the LUT-based correction method allowed for precise MR thermometry during the ablation procedure (temperature standard deviation <3 °C). No unwanted heating in the near field (i.e. skin) nor in the far field (pectoral muscle) was detected.The newly developed dedicated breast MR-HIFU system allows for safe, accurate and precise ablation of breast tumors.

Understanding ultrasound induced sonoporation: definitions and underlying mechanisms.

In the past two decades, research has underlined the potential of ultrasound and microbubbles to enhance drug delivery. However, there is less consensus on the biophysical and biological mechanisms leading to this enhanced delivery. Sonoporation, i.e. the formation of temporary pores in the cell membrane, as well as enhanced endocytosis is reported. Because of the variety of ultrasound settings used and corresponding microbubble behavior, a clear overview is missing. Therefore, in this review, the mechanisms contributing to sonoporation are categorized according to three ultrasound settings: i) low intensity ultrasound leading to stable cavitation of microbubbles, ii) high intensity ultrasound leading to inertial cavitation with microbubble collapse, and iii) ultrasound application in the absence of microbubbles. Using low intensity ultrasound, the endocytotic uptake of several drugs could be stimulated, while short but intense ultrasound pulses can be applied to induce pore formation and the direct cytoplasmic uptake of drugs. Ultrasound intensities may be adapted to create pore sizes correlating with drug size. Small molecules are able to diffuse passively through small pores created by low intensity ultrasound treatment. However, delivery of larger drugs such as nanoparticles and gene complexes, will require higher ultrasound intensities in order to allow direct cytoplasmic entry.

Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation of liver tumours.

Recent decades have seen a paradigm shift in the treatment of liver tumours from invasive surgical procedures to minimally invasive image-guided ablation techniques. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a novel, completely non-invasive ablation technique that has the potential to change the field of liver tumour ablation. The image guidance, using MR imaging and MR temperature mapping, provides excellent planning images and real-time temperature information during the ablation procedure. However, before clinical implementation of MR-HIFU for liver tumour ablation is feasible, several organ-specific challenges have to be addressed. In this review we discuss the MR-HIFU ablation technique, the liver-specific challenges for MR-HIFU tumour ablation, and the proposed solutions for clinical translation.

The PRESTO technique for fMRI.

In the early days of BOLD fMRI, the acquisition of T(2)(*) weighted data was greatly facilitated by rapid scan techniques such as EPI. The latter, however, was only available on a few MRI systems that were equipped with specialized hardware that allowed rapid switching of the imaging gradients. For this reason, soon after the invention of fMRI, the scan technique PRESTO was developed to make rapid T(2)(*) weighted scanning available on standard clinical scanners. This method combined echo shifting, which allows for echo times longer than the sequence repetition time, with acquisition of multiple k-space lines per excitation. These two concepts were combined in order to achieve a method fast enough for fMRI, while maintaining a sufficiently long echo time for optimal contrast. PRESTO has been primarily used for 3D scanning, which minimized the contribution of large vessels due to inflow effects. Although PRESTO is still being used today, its appeal has lessened somewhat due to increased gradient performance of modern MRI scanners. Compared to 2D EPI, PRESTO may have somewhat reduced temporal stability, which is a disadvantage for fMRI that may not outweigh the advantage of reduced inflow effects provided by 3D scanning. In this overview, the history of the development of the PRESTO is presented, followed by a qualitative comparison with EPI.

Towards optimized MR thermometry of the human heart at 3T.

Catheter ablation using radio frequency (RF) has been used increasingly for the treatment of cardiac arrhythmias and may be combined with proton resonance frequency shift (PRFS) -based MR thermometry to determine the therapy endpoint. We evaluated the suitability of two different MR thermometry sequences (TFE and TFE-EPI) and three blood suppression techniques. Experiments were performed without heating, using an optimized imaging protocol including navigator respiratory compensation, cardiac triggering, and image processing for the compensation of motion and susceptibility artefacts. Blood suppression performance and its effect on temperature stability were evaluated in the ventricular septum of eight healthy volunteers using multislice double inversion recovery (MDIR), motion sensitized driven equilibrium (MSDE), and inflow saturation by saturation slabs (IS). It was shown that blood suppression during MR thermometry improves the contrast-to-noise ratio (CNR), the robustness of the applied motion correction algorithm as well as the temperature stability. A gradient echo sequence accelerated by an EPI readout and parallel imaging (SENSE) and using inflow saturation blood suppression was shown to achieve the best results. Temperature stabilities of 2 °C or better in the ventricular septum with a spatial resolution of 3.5 × 3.5 × 8mm(3) and a temporal resolution corresponding to the heart rate of the volunteer, were observed. Our results indicate that blood suppression improves the temperature stability when performing cardiac MR thermometry. The proposed MR thermometry protocol, which optimizes temperature stability in the ventricular septum, represents a step towards PRFS-based MR thermometry of the heart at 3 T.

Simultaneous T1 measurements and proton resonance frequency shift based thermometry using variable flip angles.

A method is presented which allows precise temperature and longitudinal (T(1)) relaxation time measurements with high spatial and temporal resolution. This is achieved by combining dynamic variable flip angle based T(1) relaxation mapping with proton resonance frequency shift based thermometry. Herein, dynamic T(1) mapping is either used as a complementary measure of temperature or for the detection of T(1) contrast agent release. For the first application, the temperature evolution during a high-intensity focused ultrasound tissue ablation experiment was measured in both, porcine fat and muscle, simultaneously. In this application, temperature accuracies of 2.5 K for T(1)-based thermometry in fat and 1.2 K for proton resonance frequency shift-based thermometry in muscle were observed. The second application relates to MR-guidance of high-intensity focused ultrasound-induced local drug delivery by means of thermo-sensitive liposomes labeled with a T(1) contrast agent (Gd-HPDO3A). When the measured temperature exceeded the phase transition temperature of the liposomes, T(1) was observed to decrease with a good temporal and spatial correlation due to the release of Gd-HPDO3A. The presented results demonstrate the feasibility of the proposed method for two important applications in MR-guided noninvasive therapy. It offers a high temporal resolution when compared with interleaved Look-Locker based T(1) mapping techniques and thus represents an interesting candidate for simultaneous real-time monitoring of T(1) and temperature changes.

Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes.

A novel two-step protocol for intracellular drug delivery has been evaluated in vitro. As a first step TO-PRO-3 (a cell-impermeable dye that displays a strong fluorescence enhancement upon binding to nucleic acids) encapsulated in thermosensitive liposomes was released after heating to 42°C. A second step consisted of ultrasound-mediated local permeabilization of cell membrane allowing TO-PRO-3 internalization observable as nuclear staining. Only the combination of two consecutive steps - heating and sonication in the presence of SonoVue microbubbles led to the model drug TO-PRO-3 release from the thermosensitive liposomes and its intracellular uptake. This protocol is potentially beneficial for the intracellular delivery of cell impermeable drugs that suffer from rapid clearance and/or degradation in blood and are not intrinsically taken up by cells.

Online correction of respiratory-induced field disturbances for continuous MR-thermometry in the breast.

MR-thermometry allows monitoring of the local temperature evolution during minimally invasive interventional therapies. However, for the particular case of MR-thermometry in the human breast, magnetic field variations induced by the respiratory cycle lead to phase fluctuations requiring a suitable correction strategy to prevent thermometry errors. For this purpose a look-up-table-based multibaseline approach as well as a model-based correction algorithm were applied to MR-thermometry to correct for the periodic magnetic field changes. The proposed correction method is compatible with a variety of sensors monitoring the current respiratory state. The ability to remove phase artefacts during MR-thermometry of the human breast was demonstrated experimentally in five healthy volunteers during 3 min of free-breathing using pencil-beam navigators for respiratory control. An increase of 170-530% in temperature precision was observed for the look-up-table-based approach, whereas a further improvement by 16-36% could be achieved by applying the extended model-based correction.

Pharmacological control of head motion during cerebral blood flow imaging with CT or MRI.

Uncontrolled head motion during CT/MRI cerebral blood flow (CBF) imaging has been estimated between 3 and 15% of the cases. We present a pharmacological approach which permitted us to maintain the incident at 0.06% with few side effects. The protocol involves the systematic use of general anesthesia (sevoflurane) in children below five years and those with mental retardation. In anxious, claustrophobic or agitated adults, mild sedation with propofol, midazolam or hydroxyzine was used with mild effects on CBF. We strongly recommend the availability of basic cardiorespiratory resuscitation equipment and a recovery room before any sedation or general anesthesia is undertaken.