Nick Todd

Ultrasound-Mediated Tumor Imaging and Nanotherapy using Drug Loaded, Block Copolymer Stabilized Perfluorocarbon Nanoemulsions

Perfluorocarbon nanoemulsions can deliver lipophilic therapeutic agents to solid tumors and simultaneously provide for monitoring nanocarrier biodistribution via ultrasonography and/or (19)F MRI. In the first generation of block copolymer stabilized perfluorocarbon nanoemulsions, perfluoropentane (PFP) was used as the droplet forming compound. Although manifesting excellent therapeutic and ultrasound imaging properties, PFP nanoemulsions were unstable at storage, difficult to handle, and underwent hard to control phenomenon of irreversible droplet-to-bubble transition upon injection. To solve the above problems, perfluoro-15-crown-5-ether (PFCE) was used as a core forming compound in the second generation of block copolymer stabilized perfluorocarbon nanoemulsions. PFCE nanodroplets manifest both ultrasound and fluorine ((19)F) MR contrast properties, which allows using multimodal imaging and (19)F MR spectroscopy for monitoring nanodroplet pharmacokinetics and biodistribution. In the present paper, acoustic, imaging, and therapeutic properties of unloaded and paclitaxel (PTX) loaded PFCE nanoemulsions are reported. As manifested by the (19)F MR spectroscopy, PFCE nanodroplets are long circulating, with about 50% of the injected dose remaining in circulation 2h after the systemic injection. Sonication with 1-MHz therapeutic ultrasound triggered reversible droplet-to-bubble transition in PFCE nanoemulsions. Microbubbles formed by acoustic vaporization of nanodroplets underwent stable cavitation. The nanodroplet size (200nm to 350nm depending on a type of the shell and conditions of emulsification) as well as long residence in circulation favored their passive accumulation in tumor tissue that was confirmed by ultrasonography. In the breast and pancreatic cancer animal models, ultrasound-mediated therapy with paclitaxel-loaded PFCE nanoemulsions showed excellent therapeutic properties characterized by tumor regression and suppression of metastasis. Anticipated mechanisms of the observed effects are discussed.

Evaluation of 2D multiband EPI imaging for high-resolution, whole-brain, task-based fMRI studies at 3T: Sensitivity and slice leakage artifacts

Functional magnetic resonance imaging (fMRI) studies that require high-resolution whole-brain coverage have long scan times that are primarily driven by the large number of thin slices acquired. Two-dimensional multiband echo-planar imaging (EPI) sequences accelerate the data acquisition along the slice direction and therefore represent an attractive approach to such studies by improving the temporal resolution without sacrificing spatial resolution. In this work, a 2D multiband EPI sequence was optimized for 1.5 mm isotropic whole-brain acquisitions at 3 T with 10 healthy volunteers imaged while performing simultaneous visual and motor tasks. The performance of the sequence was evaluated in terms of BOLD sensitivity and false-positive activation at multiband (MB) factors of 1, 2, 4, and 6, combined with in-plane GRAPPA acceleration of 2 × (GRAPPA 2), and the two reconstruction approaches of Slice-GRAPPA and Split Slice-GRAPPA. Sensitivity results demonstrate significant gains in temporal signal-to-noise ratio (tSNR) and t-score statistics for MB 2, 4, and 6 compared to MB 1. The MB factor for optimal sensitivity varied depending on anatomical location and reconstruction method. When using Slice-GRAPPA reconstruction, evidence of false-positive activation due to signal leakage between simultaneously excited slices was seen in one instance, 35 instances, and 70 instances over the ten volunteers for the respective accelerations of MB 2 × GRAPPA 2, MB 4 × GRAPPA 2, and MB 6 × GRAPPA 2. The use of Split Slice-GRAPPA reconstruction suppressed the prevalence of false positives significantly, to 1 instance, 5 instances, and 5 instances for the same respective acceleration factors. Imaging protocols using an acceleration factor of MB 2 × GRAPPA 2 can be confidently used for high-resolution whole-brain imaging to improve BOLD sensitivity with very low probability for false-positive activation due to slice leakage. Imaging protocols using higher acceleration factors (MB 3 or MB 4 × GRAPPA 2) can likely provide even greater gains in sensitivity but should be carefully optimized to minimize the possibility of false activations.

The effects of spatial sampling choices on MR temperature measurements

The purpose of this article is to quantify the effects that spatial sampling parameters have on the accuracy of magnetic resonance temperature measurements during high intensity focused ultrasound treatments. Spatial resolution and position of the sampling grid were considered using experimental and simulated data for two different types of high intensity focused ultrasound heating trajectories (a single point and a 4‐mm circle) with maximum measured temperature and thermal dose volume as the metrics. It is demonstrated that measurement accuracy is related to the curvature of the temperature distribution, where regions with larger spatial second derivatives require higher resolution. The location of the sampling grid relative temperature distribution has a significant effect on the measured values. When imaging at 1.0 × 1.0 × 3.0 mm3 resolution, the measured values for maximum temperature and volume dosed to 240 cumulative equivalent minutes (CEM) or greater varied by 17% and 33%, respectively, for the single‐point heating case, and by 5% and 18%, respectively, for the 4‐mm circle heating case. Accurate measurement of the maximum temperature required imaging at 1.0 × 1.0 × 3.0 mm3 resolution for the single‐point heating case and 2.0 × 2.0 × 5.0 mm3 resolution for the 4‐mm circle heating case. Magn Reson Med, 2011.

Model predictive filtering for improved temporal resolution in MRI temperature imaging.

A novel method for reconstructing MRI temperature maps from undersampled data is presented. The method, model predictive filtering, combines temperature predictions from a preidentified thermal model with undersampled k‐space data to create temperature maps in near real time. The model predictive filtering algorithm was implemented in three ways: using retrospectively undersampled k‐space data from a fully sampled two‐dimensional gradient echo (GRE) sequence (reduction factors R = 2.7 to R = 7.1), using actually undersampled data from a two‐dimensional GRE sequence (R = 4.8), and using actually undersampled data from a three‐dimensional GRE sequence (R = 12.1). Thirty‐nine high‐intensity focused ultrasound heating experiments were performed under MRI monitoring to test the model predictive filtering technique against the current gold standard for MR temperature mapping, the proton resonance frequency shift method. For both of the two‐dimensional implementations, the average error over the five hottest voxels from the hottest time frame remained between ±0.8°C and the temperature root mean square error over a 24 × 7 × 3 × 25‐voxel region of interest remained below 0.35°C. The largest errors for the three‐dimensional implementation were slightly worse: −1.4°C for the mean error of the five hottest voxels and 0.61°C for the temperature root mean square error. Magn Reson Med 63:1269–1279, 2010.

Temporally constrained reconstruction applied to MRI temperature data

The monitoring of thermal ablation procedures would benefit from an acceleration in the rate at which MRI temperature maps are acquired. Constrained reconstruction techniques have been shown to be capable of generating high quality images using only a fraction of the k‐space data. Here, we present a temporally constrained reconstruction (TCR) algorithm applied to proton resonance frequency shift (PRF) data. The algorithm generates images from undersampled data by iteratively minimizing a cost function. The unique challenges of using an iterative constrained reconstruction technique to generate real‐time images were addressed. For a set of eight heating experiments on ex vivo porcine tissue, a maximum reduction factor of 4 was achieved while keeping the root mean square error (RMSE) of the temperature below 0.5°C. For a set of three heating experiments on in vivo canine muscle tissue, the maximum reduction factor achieved was 3 while keeping the temperature RMSE below 1.0°C. At these reduction factors, the TCR algorithm underpredicted the thermal dose by an average of 6% for the ex vivo data and 28% for the in vivo data. Compared with sliding window and low resolution reconstructions, the RMSE of the TCR algorithm was significantly lower (P < 0.05 in all cases). Magn Reson Med, 2009.

Design and characterization of a laterally mounted phased-array transducer breast-specific MRgHIFU device with integrated 11-channel receiver array

PURPOSE This work presents the design and preliminary evaluation of a new laterally mounted phased-array MRI-guided high-intensity focused ultrasound (MRgHIFU) system with an integrated 11-channel phased-array radio frequency (RF) coil intended for breast cancer treatment. The design goals for the system included the ability to treat the majority of tumor locations, to increase the MR images signal-to-noise ratio (SNR) throughout the treatment volume and to provide adequate comfort for the patient. METHODS In order to treat the majority of the breast volume, the device was designed such that the treated breast is suspended in a 17-cm diameter treatment cylinder. A laterally shooting 1-MHz, 256-element phased-array ultrasound transducer with flexible positioning is mounted outside the treatment cylinder. This configuration achieves a reduced water volume to minimize RF coil loading effects, to position the coils closer to the breast for increased signal sensitivity, and to reduce the MR image noise associated with using water as the coupling fluid. This design uses an 11-channel phased-array RF coil that is placed on the outer surface of the cylinder surrounding the breast. Mechanical positioning of the transducer and electronic steering of the focal spot enable placement of the ultrasound focus at arbitrary locations throughout the suspended breast. The treatment platform allows the patient to lie prone in a face-down position. The system was tested for comfort with 18 normal volunteers and SNR capabilities in one normal volunteer and for heating accuracy and stability in homogeneous phantom and inhomogeneous ex vivo porcine tissue. RESULTS There was a 61% increase in mean relative SNR achieved in a homogeneous phantom using the 11-channel RF coil when compared to using only a single-loop coil around the chest wall. The repeatability of the systems energy delivery in a single location was excellent, with less than 3% variability between repeated temperature measurements at the same location. The execution of a continuously sonicated, predefined 48-point, 8-min trajectory path resulted in an ablation volume of 8.17 cm(3), with one standard deviation of 0.35 cm(3) between inhomogeneous ex vivo tissue samples. Comfort testing resulted in negligible side effects for all volunteers. CONCLUSIONS The initial results suggest that this new device will potentially be suitable for MRgHIFU treatment in a wide range of breast sizes and tumor locations.

An evaluation of prospective motion correction (PMC) for high resolution quantitative MRI

Quantitative imaging aims to provide in vivo neuroimaging biomarkers with high research and diagnostic value that are sensitive to underlying tissue microstructure. In order to use these data to examine intra-cortical differences or to define boundaries between different myelo-architectural areas, high resolution data are required. The quality of such measurements is degraded in the presence of motion hindering insight into brain microstructure. Correction schemes are therefore vital for high resolution, whole brain coverage approaches that have long acquisition times and greater sensitivity to motion. Here we evaluate the use of prospective motion correction (PMC) via an optical tracking system to counter intra-scan motion in a high resolution (800 μm isotropic) multi-parameter mapping (MPM) protocol. Data were acquired on six volunteers using a 2 × 2 factorial design permuting the following conditions: PMC on/off and motion/no motion. In the presence of head motion, PMC-based motion correction considerably improved the quality of the maps as reflected by fewer visible artifacts and improved consistency. The precision of the maps, parameterized through the coefficient of variation in cortical sub-regions, showed improvements of 11–25% in the presence of deliberate head motion. Importantly, in the absence of motion the PMC system did not introduce extraneous artifacts into the quantitative maps. The PMC system based on optical tracking offers a robust approach to minimizing motion artifacts in quantitative anatomical imaging without extending scan times. Such a robust motion correction scheme is crucial in order to achieve the ultra-high resolution required of quantitative imaging for cutting edge in vivo histology applications.

Reconstruction of fully three‐dimensional high spatial and temporal resolution MR temperature maps for retrospective applications

Many areas of MR‐guided thermal therapy research would benefit from temperature maps with high spatial and temporal resolution that cover a large three‐dimensional volume. This article describes an approach to achieve these goals, which is suitable for research applications where retrospective reconstruction of the temperature maps is acceptable. The method acquires undersampled data from a modified three‐dimensional segmented echo‐planar imaging sequence and creates images using a temporally constrained reconstruction algorithm. The three‐dimensional images can be zero‐filled to arbitrarily small voxel spacing in all directions and then converted into temperature maps using the standard proton resonance frequency shift technique. During high intensity focused ultrasound heating experiments, the proposed method was used to obtain temperature maps with 1.5 mm × 1.5 mm × 3.0 mm resolution, 288 mm × 162 mm × 78 mm field of view, and 1.7 s temporal resolution. The approach is validated to demonstrate that it can accurately capture the spatial characteristics and time dynamics of rapidly changing high intensity focused ultrasound‐induced temperature distributions. Example applications from MR‐guided high intensity focused ultrasound research are shown to demonstrate the benefits of the large coverage fully three‐dimensional temperature maps, including characterization of volumetric heating trajectories and near‐ and far‐field heating. Magn Reson Med, 2012.

Toward Real-Time Availability of 3D Temperature Maps Created with Temporally Constrained Reconstruction

To extend the previously developed temporally constrained reconstruction (TCR) algorithm to allow for real‐time availability of three‐dimensional (3D) temperature maps capable of monitoring MR‐guided high intensity focused ultrasound applications.

Prospective motion correction of 3D echo-planar imaging data for functional MRI using optical tracking

We evaluated the performance of an optical camera based prospective motion correction (PMC) system in improving the quality of 3D echo-planar imaging functional MRI data. An optical camera and external marker were used to dynamically track the head movement of subjects during fMRI scanning. PMC was performed by using the motion information to dynamically update the sequences RF excitation and gradient waveforms such that the field-of-view was realigned to match the subjects head movement. Task-free fMRI experiments on five healthy volunteers followed a 2 × 2 × 3 factorial design with the following factors: PMC on or off; 3.0 mm or 1.5 mm isotropic resolution; and no, slow, or fast head movements. Visual and motor fMRI experiments were additionally performed on one of the volunteers at 1.5 mm resolution comparing PMC on vs PMC off for no and slow head movements. Metrics were developed to quantify the amount of motion as it occurred relative to k-space data acquisition. The motion quantification metric collapsed the very rich camera tracking data into one scalar value for each image volume that was strongly predictive of motion-induced artifacts. The PMC system did not introduce extraneous artifacts for the no motion conditions and improved the time series temporal signal-to-noise by 30% to 40% for all combinations of low/high resolution and slow/fast head movement relative to the standard acquisition with no prospective correction. The numbers of activated voxels (p < 0.001, uncorrected) in both task-based experiments were comparable for the no motion cases and increased by 78% and 330%, respectively, for PMC on versus PMC off in the slow motion cases. The PMC system is a robust solution to decrease the motion sensitivity of multi-shot 3D EPI sequences and thereby overcome one of the main roadblocks to their widespread use in fMRI studies.