Publications

2009
Colucci V, Strichartz G, Jolesz FA, Vykhodtseva N, Hynynen K. Focused Ultrasound Effects on Nerve Action Potential in Vitro. Ultrasound Med Biol. 2009;35 (10) :1737-47.Abstract

Minimally invasive applications of thermal and mechanical energy to selective areas of the human anatomy have led to significant advances in treatment of and recovery from typical surgical interventions. Image-guided focused ultrasound allows energy to be deposited deep into the tissue, completely noninvasively. There has long been interest in using this focal energy delivery to block nerve conduction for pain control and local anesthesia. In this study, we have performed an in vitro study to further extend our knowledge of this potential clinical application. The sciatic nerves from the bullfrog (Rana catesbeiana) were subjected to focused ultrasound (at frequencies of 0.661 MHz and 1.986 MHz) and to heated Ringer's solution. The nerve action potential was shown to decrease in the experiments and correlated with temperature elevation measured in the nerve. The action potential recovered either completely, partially or not at all, depending on the parameters of the ultrasound exposure. The reduction of the baseline nerve temperature by circulating cooling fluid through the sonication chamber did not prevent the collapse of the nerve action potential; but higher power was required to induce the same endpoint as without cooling. These results indicate that a thermal mechanism of focused ultrasound can be used to block nerve conduction, either temporarily or permanently.

Mulkern RV, Haker SJ, Maier SE. On High b Diffusion Imaging in the Human Brain: Ruminations and Experimental Insights. Magn Reson Imaging. 2009;27 (8) :1151-62.Abstract

Interest in the manner in which brain tissue signal decays with b factor in diffusion imaging schemes has grown in recent years following the observation that the decay curves depart from purely monoexponential decay behavior. Regardless of the model or fitting function proposed for characterizing sufficiently sampled decay curves (vide infra), the departure from monoexponentiality spells increased tissue characterization potential. The degree to which this potential can be harnessed to improve specificity, sensitivity and spatial localization of diseases in brain, and other tissues, largely remains to be explored. Furthermore, the degree to which currently popular diffusion tensor imaging methods, including visually impressive white matter fiber "tractography" results, have almost completely ignored the nonmonoexponential nature of the basic signal decay with b factor is worthy of communal introspection. Here we limit our attention to a review of the basic experimental features associated with brain water signal diffusion decay curves as measured over extended b-factor ranges, the simple few parameter fitting functions that have been proposed to characterize these decays and the more involved models, e.g.,"ruminations," which have been proposed to account for the nonmonoexponentiality to date.

Jagannathan J, Sanghvi NT, Crum LA, Yen C-P, Medel R, Dumont AS, Sheehan JP, Steiner L, Jolesz FA, Kassell NF. High-intensity focused ultrasound surgery of the brain: part 1--A historical perspective with modern applications. Neurosurgery. 2009;64 (2) :201-10; discussion 210-1.Abstract

The field of magnetic resonance imaging-guided high-intensity focused ultrasound surgery (MRgFUS) is a rapidly evolving one, with many potential applications in neurosurgery. The first of 3 articles on MRgFUS, this article focuses on the historical development of the technology and its potential applications in modern neurosurgery. The evolution of MRgFUS has occurred in parallel with modern neurological surgery, and the 2 seemingly distinct disciplines share many of the same pioneering figures. Early studies on focused ultrasound treatment in the 1940s and 1950s demonstrated the ability to perform precise lesioning in the human brain, with a favorable risk-benefit profile. However, the need for a craniotomy, as well as the lack of sophisticated imaging technology, resulted in limited growth of high-intensity focused ultrasound for neurosurgery. More recently, technological advances have permitted the combination of high-intensity focused ultrasound along with magnetic resonance imaging guidance to provide an opportunity to effectively treat a variety of central nervous system disorders. Although challenges remain, high-intensity focused ultrasound-mediated neurosurgery may offer the ability to target and treat central nervous system conditions that were previously extremely difficult to address. The remaining 2 articles in this series will focus on the physical principles of modern MRgFUS as well as current and future avenues for investigation.

Shen S-H, Fennessy FM, McDannold N, Jolesz FA, Tempany CM. Image-guided Thermal Therapy of Uterine Fibroids. Semin Ultrasound CT MR. 2009;30 (2) :91-104.Abstract

Thermal ablation is an established treatment for tumors. The merging of newly developed imaging techniques has allowed precise targeting and real-time thermal mapping. This article provides an overview of the image-guided thermal ablation techniques in the treatment of uterine fibroids. Background on uterine fibroids, including epidemiology, histology, symptoms, imaging findings, and current treatment options, is first outlined. After describing the principle of magnetic resonance thermal imaging, we introduce the applications of image-guided thermal therapies, including laser ablation, radiofrequency ablation, cryotherapy, and in particular, magnetic resonance-guided focused ultrasound surgery, and how they apply to uterine fibroid treatment.

White JP, Whalen S, Tang SC, Clement GT, Jolesz FA, Golby AJ. An intraoperative brain shift monitor using shear mode transcranial ultrasound: preliminary results. J Ultrasound Med. 2009;28 (2) :191-203.Abstract

OBJECTIVE: Various methods of intraoperative structural monitoring during neurosurgery are used to localize lesions after brain shift and to guide surgically introduced probes such as biopsy needles or stimulation electrodes. With its high temporal resolution, portability, and nonionizing mode of radiation, ultrasound has potential advantages over other existing imaging modalities for intraoperative monitoring, yet ultrasound is rarely used during neurosurgery largely because of the craniotomy requirement to achieve sufficiently useful signals. METHODS: Prompted by results from recent studies on transcranial ultrasound, a prototype device that aims to use the shear mode of transcranial ultrasound transmission for intraoperative monitoring was designed, constructed, and tested with 10 human participants. Magnetic resonance images were then obtained with the device spatially registered to the magnetic resonance imaging (MRI) reference coordinates. Peaks in both the ultrasound and MRI signals were identified and analyzed for both spatial localization and signal-to-noise ratio (SNR). RESULTS: The first results aimed toward validating the prototype device with MRI showed an excellent correlation (n = 38; R(2) = 0.9962) between the structural localization abilities of the two modalities. In addition, the overall SNR of the ultrasound backscatter signals (n = 38; SNR = 25.4 +/- 5.2 dB, mean +/- SD) was statistically equivalent to that of the MRI data (n = 38; SNR = 22.5 +/- 4.8 dB). CONCLUSIONS: A statistically significant correlation of localized intracranial structures between intraoperative transcranial ultrasound monitoring and MRI data was achieved with 10 human participants. We have shown and validated a prototype device incorporating transcranial shear mode ultrasound for clinical monitoring applications.

Oguro S, Tokuda J, Elhawary H, Haker S, Kikinis R, Tempany CM, Hata N. MRI signal intensity based B-spline nonrigid registration for pre- and intraoperative imaging during prostate brachytherapy. J Magn Reson Imaging. 2009;30 (5) :1052-8.Abstract

PURPOSE: To apply an intensity-based nonrigid registration algorithm to MRI-guided prostate brachytherapy clinical data and to assess its accuracy. MATERIALS AND METHODS: A nonrigid registration of preoperative MRI to intraoperative MRI images was carried out in 16 cases using a Basis-Spline algorithm in a retrospective manner. The registration was assessed qualitatively by experts' visual inspection and quantitatively by measuring the Dice similarity coefficient (DSC) for total gland (TG), central gland (CG), and peripheral zone (PZ), the mutual information (MI) metric, and the fiducial registration error (FRE) between corresponding anatomical landmarks for both the nonrigid and a rigid registration method. RESULTS: All 16 cases were successfully registered in less than 5 min. After the nonrigid registration, DSC values for TG, CG, PZ were 0.91, 0.89, 0.79, respectively, the MI metric was -0.19 +/- 0.07 and FRE presented a value of 2.3 +/- 1.8 mm. All the metrics were significantly better than in the case of rigid registration, as determined by one-sided t-tests. CONCLUSION: The intensity-based nonrigid registration method using clinical data was demonstrated to be feasible and showed statistically improved metrics when compare to only rigid registration. The method is a valuable tool to integrate pre- and intraoperative images for brachytherapy.

Pilatou MC, Stewart EA, Maier SE, Fennessy FM, Hynynen K, Tempany CM, McDannold N. MRI-based thermal dosimetry and diffusion-weighted imaging of MRI-guided focused ultrasound thermal ablation of uterine fibroids. J Magn Reson Imaging. 2009;29 (2) :404-11.Abstract

PURPOSE: To investigate tissue changes observed in diffusion-weighted imaging (DWI) and its relation to contrast imaging, thermal dosimetry, and changes in the apparent diffusion coefficient (ADC) after MRI-guided focused ultrasound surgery (MRgFUS) of uterine fibroids. MATERIALS AND METHODS: Imaging data were analyzed from 45 fibroids in 42 women treated with MRgFUS. The areas of the hyperintense regions in DWI and of nonperfused regions in T1-weighted contrast enhanced imaging (both acquired immediately after treatment) were compared with each other and to thermal dosimetry based estimates. Changes in ADC were also calculated. RESULTS: Hyperintense regions were observed in 35/45 fibroids in DWI. When present, the areas of these regions were comparable on average to the thermal dose estimates and to the nonperfused regions, except for in several large treatments in which the nonperfused region extended beyond the treated area. ADC increased in 19 fibroids and decreased in the others. CONCLUSION: DWI changes, which includes changes in both in T2 and ADC, may be useful in many cases to delineate the treated region resulting from MRgFUS. However, clear DWI changes were not always observed, and in some large treatments, the extent of the nonperfused region was under estimated. ADC changes immediately after MRgFUS were unpredictable.

Tokuda J, Fischer GS, Papademetris X, Yaniv Z, Ibanez L, Cheng P, Liu H, Blevins J, Arata J, Golby AJ, et al. OpenIGTLink: An Open Network Protocol for Image-guided Therapy Environment. Int J Med Robot. Int J Med Robot. 2009;5 (4) :423-34.Abstract

BACKGROUND: With increasing research on system integration for image-guided therapy (IGT), there has been a strong demand for standardized communication among devices and software to share data such as target positions, images and device status. METHOD: We propose a new, open, simple and extensible network communication protocol for IGT, named OpenIGTLink, to transfer transform, image and status messages. We conducted performance tests and use-case evaluations in five clinical and engineering scenarios. RESULTS: The protocol was able to transfer position data with submillisecond latency up to 1024 fps and images with latency of <10 ms at 32 fps. The use-case tests demonstrated that the protocol is feasible for integrating devices and software. CONCLUSION: The protocol proved capable of handling data required in the IGT setting with sufficient time resolution and latency. The protocol not only improves the interoperability of devices and software but also promotes transitions of research prototypes to clinical applications.

Nguyen PL, Chen RC, Clark JA, Cormack RA, Loffredo M, McMahon E, Nguyen AU, Suh WW, Tempany CM, D'Amico AV. Patient-reported Quality of Life after Salvage Brachytherapy for Radio-recurrent Prostate Cancer: A Prospective Phase II Study. Brachytherapy. 2009;8 (4) :345-52.Abstract

BACKGROUND: Patient-reported quality of life (QOL) after salvage brachytherapy for radiorecurrent prostate cancer has not been well-characterized prospectively. METHODS: We examined 25 men who recurred after primary radiotherapy for prostate cancer and received MRI-guided salvage brachytherapy as part of a prospective Phase II study. These patients received prospectively a validated patient-reported QOL questionnaire to fill out at baseline, as well as 3, 15, and 27 months after re-irradiation to determine the degree of sexual, bowel, and urinary dysfunction (maximum dysfunction score=100). RESULTS: On average, sexual function continued to decline with time, and patients had significantly worse sexual function scores at 27 months than baseline (p=0.01). Although bowel and urinary symptoms worsened acutely at 3 or 15 months, they showed on average some improvement by 27 months, and there were no significant differences between baseline and 27-month urinary or bowel scores. An interval to re-irradiation less than 4.5 years and prior brachytherapy were each associated significantly with the largest decrements in bowel function (p=0.035). CONCLUSION: Similar to the patterns seen in the de novo setting, patients who receive salvage brachytherapy report a worsening of bowel and urinary symptoms followed by some improvement by 27 months, while sexual function steadily declines over time. Interval to re-irradiation and type of prior radiation received may be used to counsel and optimize selection of men for salvage brachytherapy with regard to QOL endpoints.

Suarez RO, Whalen S, Nelson AP, Tie Y, Meadows M-E, Radmanesh A, Golby AJ. Threshold-independent Functional MRI Determination of Language Dominance: A Validation Study Against Clinical Gold Standards. Epilepsy Behav. 2009;16 (2) :288-97.Abstract

Functional MRI (fMRI) is often used for presurgical language lateralization. In the most common approach, a laterality index (LI) is calculated on the basis of suprathreshold voxels. However, strong dependencies between LI and threshold can diminish the effectiveness of this technique; in this study we investigated an original methodology that is independent of threshold. We compared this threshold-independent method against the common threshold-dependent method in 14 patients with epilepsy who underwent Wada testing. In addition, clinical results from electrocortical language mapping and postoperative language findings were used to assess the validity of the fMRI lateralization method. The threshold-dependent methodology yielded ambiguous or incongruent lateralization outcomes in 4 of 14 patients in the inferior frontal gyrus (IFG) and in 6 of 14 patients in the supramarginal gyrus (SMG). Conversely, the threshold-independent method yielded unambiguous lateralization in all the patients tested, and demonstrated lateralization outcomes incongruent with clinical standards in 2 of 14 patients in IFG and in 1 of 14 patients in SMG. This validation study demonstrates that the threshold-dependent LI calculation is prone to significant within-patient variability that could render results unreliable; the threshold-independent method can generate distinct LIs that are more concordant with gold standard clinical findings.

San José Estépar R, Westin C-F, Vosburgh KG. Towards real time 2D to 3D registration for ultrasound-guided endoscopic and laparoscopic procedures. Int J Comput Assist Radiol Surg. 2009;4 (6) :549-60.Abstract

PURPOSE: A method to register endoscopic and laparoscopic ultrasound (US) images in real time with pre-operative computed tomography (CT) data sets has been developed with the goal of improving diagnosis, biopsy guidance, and surgical interventions in the abdomen. METHODS: The technique, which has the potential to operate in real time, is based on a new phase correlation technique: LEPART, which specifies the location of a plane in the CT data which best corresponds to the US image. Validation of the method was carried out using an US phantom with cyst regions and with retrospective analysis of data sets from animal model experiments. RESULTS: The phantom validation study shows that local translation displacements can be recovered for each US frame with a root mean squared error of 1.56 +/- 0.78 mm in less than 5 sec, using non-optimized algorithm implementations. CONCLUSION: A new method for multimodality (preoperative CT and intraoperative US endoscopic images) registration to guide endoscopic interventions was developed and found to be efficient using clinically realistic datasets. The algorithm is inherently capable of being implemented in a parallel computing system so that full real time operation appears likely.

2008
Lee J-H, O'Leary HM, Park HW, Jolesz FA, Yoo S-S. Atlas-based multichannel monitoring of functional MRI signals in real-time: automated approach. Hum Brain Mapp. 2008;29 (2) :157-66.Abstract
We report an automated method to simultaneously monitor blood-oxygenation-level-dependent (BOLD) MR signals from multiple cortical areas in real-time. Individual brain anatomy was normalized and registered to a pre-segmented atlas in standardized anatomical space. Subsequently, using real-time fMRI (rtfMRI) data acquisition, localized BOLD signals were measured and displayed from user-selected areas labeled with anatomical and Brodmann's Area (BA) nomenclature. The method was tested on healthy volunteers during the performance of hand motor and internal speech generation tasks employing a trial-based design. Our data normalization and registration algorithm, along with image reconstruction, movement correction and a data display routine were executed with enough processing and communication bandwidth necessary for real-time operation. Task-specific BOLD signals were observed from the hand motor and language areas. One of the study participants was allowed to freely engage in hand clenching tasks, and associated brain activities were detected from the motor-related neural substrates without prior knowledge of the task onset time. The proposed method may be applied to various applications such as neurofeedback, brain-computer-interface, and functional mapping for surgical planning where real-time monitoring of region-specific brain activity is needed.
McDannold N, Vykhodtseva N, Hynynen K. Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index. Ultrasound Med Biol. 2008;34 (5) :834-40.Abstract
This work investigated the effect of ultrasonic frequency on the threshold for blood-brain barrier (BBB) disruption induced by ultrasound pulses combined with an ultrasound contrast agent. Experiments were performed in rabbits using pulsed sonications at 2.04 MHz with peak pressure amplitudes ranging from 0.3 to 2.3 MPa. BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The threshold for BBB disruption was estimated using probit regression. Representative samples with similar amounts of contrast enhancement were examined in light microscopy. Results from these experiments were compared with data from previous studies that used ultrasound frequencies between 0.26 and 1.63 MHz. We found that the BBB disruption threshold (value where the probability for disruption was estimated to be 50%) expressed in terms of the peak negative pressure amplitude increased as a function of the frequency. It appeared to be constant, however, when the exposures were expressed as a function of the mechanical index (peak negative pressure amplitude estimated in situ divided by square root of frequency). Regression of data from all frequencies resulted in an estimated mechanical index threshold of 0.46 (95% confidence intervals: 0.42 to 0.50). Histologic examination of representative samples with similar amounts of blood-brain barrier disruption found that the number of regions containing extravasated red blood cells per unit area was substantially lower on average for lower ultrasound frequencies. This data suggests that the mechanical index is a meaningful metric for ultrasound-induced blood-brain barrier disruption, at least for when other parameters that are not taken into account by the mechanical index are not varied. It also suggests that lower frequency sonication produces less red blood cell extravasation per unit area.
Lee J-H, Lee T-W, Jolesz FA, Yoo S-S. Independent vector analysis (IVA): multivariate approach for fMRI group study. Neuroimage. 2008;40 (1) :86-109.Abstract
Independent component analysis (ICA) of fMRI data generates session/individual specific brain activation maps without a priori assumptions regarding the timing or pattern of the blood-oxygenation-level-dependent (BOLD) signal responses. However, because of a random permutation among output components, ICA does not offer a straightforward solution for the inference of group-level activation. In this study, we present an independent vector analysis (IVA) method to address the permutation problem during fMRI group data analysis. In comparison to ICA, IVA offers an analysis of additional dependent components, which were assigned for use in the automated grouping of dependent activation patterns across subjects. Upon testing using simulated trial-based fMRI data, our proposed method was applied to real fMRI data employing both a single-trial task-paradigm (right hand motor clenching and internal speech generation tasks) and a three-trial task-paradigm (right hand motor imagery task). A generalized linear model (GLM) and the group ICA of the fMRI toolbox (GIFT) were also applied to the same data set for comparison to IVA. Compared to GLM, IVA successfully captured activation patterns even when the functional areas showed variable hemodynamic responses that deviated from a hypothesized response. We also showed that IVA effectively inferred group-activation patterns of unknown origins without the requirement for a pre-processing stage (such as data concatenation in ICA-based GIFT). IVA can be used as a potential alternative or an adjunct to current ICA-based fMRI group processing methods.
Talos I-F, Rubin DL, Halle M, Musen M, Kikinis R. A prototype symbolic model of canonical functional neuroanatomy of the motor system. J Biomed Inform. 2008;41 (2) :251-63.Abstract
Recent advances in bioinformatics have opened entire new avenues for organizing, integrating and retrieving neuroscientific data, in a digital, machine-processable format, which can be at the same time understood by humans, using ontological, symbolic data representations. Declarative information stored in ontological format can be perused and maintained by domain experts, interpreted by machines, and serve as basis for a multitude of decision support, computerized simulation, data mining, and teaching applications. We have developed a prototype symbolic model of canonical neuroanatomy of the motor system. Our symbolic model is intended to support symbolic look up, logical inference and mathematical modeling by integrating descriptive, qualitative and quantitative functional neuroanatomical knowledge. Furthermore, we show how our approach can be extended to modeling impaired brain connectivity in disease states, such as common movement disorders. In developing our ontology, we adopted a disciplined modeling approach, relying on a set of declared principles, a high-level schema, Aristotelian definitions, and a frame-based authoring system. These features, along with the use of the Unified Medical Language System (UMLS) vocabulary, enable the alignment of our functional ontology with an existing comprehensive ontology of human anatomy, and thus allow for combining the structural and functional views of neuroanatomy for clinical decision support and neuroanatomy teaching applications. Although the scope of our current prototype ontology is limited to a particular functional system in the brain, it may be possible to adapt this approach for modeling other brain functional systems as well.
Maddah M, Grimson EWL, Warfield SK, Wells WM. A unified framework for clustering and quantitative analysis of white matter fiber tracts. Med Image Anal. 2008;12 (2) :191-202.Abstract
We present a novel approach for joint clustering and point-by-point mapping of white matter fiber pathways. Knowledge of the point correspondence along the fiber pathways is not only necessary for accurate clustering of the trajectories into fiber bundles, but also crucial for any tract-oriented quantitative analysis. We employ an expectation-maximization (EM) algorithm to cluster the trajectories in a gamma mixture model context. The result of clustering is the probabilistic assignment of the fiber trajectories to each cluster, an estimate of the cluster parameters, i.e. spatial mean and variance, and point correspondences. The fiber bundles are modeled by the mean trajectory and its spatial variation. Point-by-point correspondence of the trajectories within a bundle is obtained by constructing a distance map and a label map from each cluster center at every iteration of the EM algorithm. This offers a time-efficient alternative to pairwise curve matching of all trajectories with respect to each cluster center. The proposed method has the potential to benefit from an anatomical atlas of fiber tracts by incorporating it as prior information in the EM algorithm. The algorithm is also capable of handling outliers in a principled way. The presented results confirm the efficiency and effectiveness of the proposed framework for quantitative analysis of diffusion tensor MRI.
Jolesz FA, McDannold N. Current status and future potential of MRI-guided focused ultrasound surgery. J Magn Reson Imaging. 2008;27 (2) :391-9.Abstract
The combination of the imaging abilities of magnetic resonance imaging (MRI) with the ability to delivery energy to targets deep in the body noninvasively with focused ultrasound presents a disruptive technology with the potential to significantly affect healthcare. MRI offers precise targeting, visualization, and quantification of temperature changes and the ability to immediately evaluate the treatment. By exploiting different mechanisms, focused ultrasound offers a range of therapies, ranging from thermal ablation to targeted drug delivery. This article reviews recent preclinical and tests clinical of this technology.
Sheikov N, McDannold N, Sharma S, Hynynen K. Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol. 2008;34 (7) :1093-104.Abstract
Previous studies have investigated a potential method for targeted drug delivery in the central nervous system that uses focused ultrasound bursts combined with an ultrasound contrast agent to temporarily disrupt the blood-brain barrier (BBB). The purpose of this work was to investigate the integrity of the tight junctions (TJs) in rat brain microvessels after this BBB disruption. Ultrasound bursts (1.5-MHz) in combination with a gas contrast agent (Optison) was applied at two locations in the brain in 25 rats to induce BBB disruption. Using immunoelectron microscopy, the distributions of the TJ-specific transmembrane proteins occludin, claudin-1, claudin-5, and of submembranous ZO-1 were examined at 1, 2, 4, 6 and 24 h after sonication. A quantitative evaluation of the protein expression was made by counting the number of immunosignals per micrometer in the junctional clefts. BBB disruption at the sonicated locations was confirmed by the leakage of i.v. administered horseradish peroxidase (HRP, m.w. 40,000 Da) and lanthanum chloride (La(3+), m.w. approximately 139 Da). Leakage of these agents was observed at 1 and 2 h and, in a few vessels, at 4 h after ultrasound application. These changes were paralleled by the apparent disintegration of the TJ complexes, as evidenced by the redistribution and loss of the immunosignals for occludin, claudin-5 and ZO-1. Claudin-1 seemed less involved. At 6 and 24 h after sonication, no HRP or lanthanum leakage was observed and the barrier function of the TJs, as indicated by the localization and density of immunosignals, appeared to be completely restored. This study provides the first direct evidence that ultrasound bursts combined with a gas contrast agent cause disassembling of the TJ molecular structure, leading to loss of the junctional barrier functions in brain microvessels. The BBB disruption appears to last up to 4 h after sonication and permits the paracellular passage of agents with molecular weights up to at least 40 kDa. These promising features can be exploited in the future development of this method that could enable the delivery of drugs, antibodies or genes to targeted locations in the brain.
McDannold N, Vykhodtseva N, Hynynen K. Effects of acoustic parameters and ultrasound contrast agent dose on focused-ultrasound induced blood-brain barrier disruption. Ultrasound Med Biol. 2008;34 (6) :930-7.Abstract
Previously, it was shown that low-intensity focused ultrasound pulses applied along with an ultrasound contrast agent results in temporary blood-brain barrier (BBB) disruption. This effect could be used for targeted drug delivery in the central nervous system. This study examined the effects of burst length, pulse repetition frequency (PRF), and ultrasound contrast agent dose on the resulting BBB disruption. One hundred nonoverlapping brain locations were sonicated through a craniotomy in experiments in 26 rabbits (ultrasound frequency: 0.69 MHz, burst: 0.1, 1, 10 ms, PRF: 0.5, 1, 2, 5 Hz, duration: 20 s, peak negative pressure amplitude: 0.1 to 1.5 MPa, Optison dosage 50, 100, 250 microl/kg). For each sonication, BBB disruption was evaluated using contrast-enhanced magnetic resonance imaging. The BBB disruption threshold (the pressure amplitude yielding a 50% probability for BBB disruption) was determined using probit regression for the three burst lengths tested. Tissue effects were examined in light microscopy for representative locations with similar amounts of contrast enhancement from each group. While changing the PRF or the Optison dosage did not result in a significant difference in the magnitude of the BBB disruption (p > 0.05), reducing the burst length resulted in significantly less contrast enhancement (p < 0.01). The BBB disruption thresholds were estimated to be 0.69, 0.47 and 0.36 MPa for 0.1, 1 and 10 ms bursts, respectively. No difference was detected in histology between any experimental groups. This data suggests that over the range of parameters tested, BBB disruption is not affected by PRF or ultrasound contrast agent dose. However, both the BBB disruption magnitude and its threshold depend on the burst length.
Farny CH, Clement GT. Feasibility of ultrasound phase contrast for heating localization. J Acoust Soc Am. 2008;123 (3) :1773-83.Abstract
Ultrasound-based methods for temperature monitoring could greatly assist focused ultrasound visualization and treatment planning based on sound speed-induced change in phase as a function of temperature. A method is presented that uses reflex transmission integration, planar projection, and tomographic reconstruction techniques to visualize phase contrast by measuring the sound field before and after heat deposition. Results from experiments and numerical simulations employing a through-transmission setup are presented to demonstrate feasibility of using phase contrast methods for identifying temperature change. A 1.088-MHz focused transducer was used to interrogate a medium with a phase contrast feature, following measurement of the baseline reference field with a hydrophone. A thermal plume in water and a tissue phantom with multiple water columns was used in separate experiments to produce a phase contrast. The reference and phase contrast field scans were numerically backprojected and the phase difference correctly identified the position and orientation of the features. The peak temperature reconstructed from the phase shift was within 0.2 degrees C of the measured temperature in the plume. Simulated results were in good agreement with experimental results. Finally, employment of reflex transmission imaging techniques for adopting a pulse-echo arrangement was simulated, and its future experimental application is discussed.

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