Publications

2006
Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A. 2006;103 (31) :11719-23.Abstract
Antibody-based anticancer agents are promising chemotherapeutic agents. Among these agents, Herceptin (trastuzumab), a humanized anti-human epidermal growth factor receptor 2 (HER2/c-erbB2) monoclonal antibody, has been used successfully in patients with breast cancer. However, in patients with brain metastasis, the blood-brain barrier limits its use, and a different delivery method is needed to treat these patients. Here, we report that Herceptin can be delivered locally and noninvasively into the mouse central nervous system through the blood-brain barrier under image guidance by using an MRI-guided focused ultrasound blood-brain barrier disruption technique. The amount of Herceptin delivered to the target tissue was correlated with the extent of the MRI-monitored barrier opening, making it possible to estimate indirectly the amount of Herceptin delivered. Histological changes attributable to this procedure were minimal. This method may represent a powerful technique for the delivery of macromolecular agents such as antibodies to treat patients with diseases of the central nervous system.
McDannold N, Tempany CM, Fennessy FM, So MJ, Rybicki FJ, Stewart EA, Jolesz FA, Hynynen K. Uterine leiomyomas: MR imaging-based thermometry and thermal dosimetry during focused ultrasound thermal ablation. Radiology. 2006;240 (1) :263-72.Abstract
PURPOSE: To retrospectively evaluate magnetic resonance (MR) imaging-based thermometry and thermal dosimetry during focused ultrasound treatments of uterine leiomyomas (ie, fibroids). MATERIALS AND METHODS: All patients gave written informed consent for the focused ultrasound treatments and the current HIPAA-compliant retrospective study, both of which were institutional review board approved. Thermometry performed during the treatments of 64 fibroids in 50 women (mean age, 46.6 years +/- 4.5 [standard deviation]) was used to create thermal dose maps. The areas that reached dose values of 240 and 18 equivalent minutes at 43 degrees C were compared with the nonperfused regions measured on contrast material-enhanced MR images by using the Bland-Altman method. Volume changes in treated fibroids after 6 months were compared with volume changes in nontreated fibroids and with MR-based thermal dose estimates. RESULTS: While the thermal dose estimates were shown to have a clear relationship with resulting nonperfused regions, the nonperfused areas were, on average, larger than the dose estimates (means of 1.9 +/- 0.7 and 1.2 +/- 0.4 times as large for areas that reached 240- and 18-minute threshold dose values, respectively). Good correlation was observed for smaller treatment volumes at the lower dose threshold (mean ratio, 1.0 +/- 0.3), but for larger treatment volumes, the nonperfused region extended to locations within the fibroid that clearly were not heated. Variations in peak temperature increase were as large as a factor of two, both between patients and within individual treatments. On average, the fibroid volume reduction at 6 months increased as the ablated volume estimated by using the thermal dose increased. CONCLUSION: Study results showed good correlation between thermal dose estimates and resulting nonperfused areas for smaller ablated volumes. For larger treatment volumes, nonperfused areas could extend within the fibroid to unheated areas.
Vykhodtseva N, McDannold N, Hynynen K. Induction of apoptosis in vivo in the rabbit brain with focused ultrasound and Optison. Ultrasound Med Biol. 2006;32 (12) :1923-9.Abstract
Histologic effects of focused ultrasound (FUS) exposures combined with an ultrasound contrast agent (Optison) were investigated to examine whether the lesions were dominated by apoptosis or necrosis. The rabbit brains (n = 17) were sonicated (1.5 MHz, peak rarefactional pressure amplitude: 1.4 to 8.8 MPa) after Optison was injected intravenously (IV). MRI and light microscopy were used to examine tissue effects. To detect apoptosis, TUNEL staining based on labeling of DNA strand breaks was used. The average number of apoptotic and necrotic cells in 300 x 220 microm microscopic fields were counted in 18 representative lesions. Lesions in the rabbit brains were created at lowered acoustic power levels when FUS was combined with Optison. In histology, the lesions exhibited red blood cell extravasations and destruction of blood vessels. At 4 h after sonication, the lesions lost many cells, and the remaining cells exhibited both necrotic and apoptotic features. Overall, apoptosis dominated; there were, on average, 32.3 +/- 13.2 apoptotic cells per microscopic field compared with only 5.1 +/- 3.4 necrotic cells per field. In conclusion, FUS combined with Optison could produce lesions that are dominated by apoptosis, presumably induced primarily via ischemia after cavitation-produced damage to the brain vasculature.
Dauguet J, Peled S, Berezovskii V, Delzescaux T, Warfield SK, Born R, Westin C-F. 3D histological reconstruction of fiber tracts and direct comparison with diffusion tensor MRI tractography. Med Image Comput Comput Assist Interv. 2006;9 (Pt 1) :109-16.Abstract
A classical neural tract tracer, WGA-HRP, was injected at multiple sites within the brain of a macaque monkey. Histological sections of the labeled fiber tracts were reconstructed in 3D, and the fibers were segmented and registered with the anatomical post-mortem MRI from the same animal. Fiber tracing along the same pathways was performed on the DTI data using a classical diffusion tracing technique. The fibers derived from the DTI were compared with those segmented from the histology in order to evaluate the performance of DTI fiber tracing. While there was generally good agreement between the two methods, our results reveal certain limitations of DTI tractography, particularly at regions of fiber tract crossing or bifurcation.
Weisenfeld NI, Mewes AUJ, Warfield SK. Highly accurate segmentation of brain tissue and subcortical gray matter from newborn MRI. Med Image Comput Comput Assist Interv. 2006;9 (Pt 1) :199-206.Abstract
The segmentation of newborn brain MRI is important for assessing and directing treatment options for premature infants at risk for developmental disorders, abnormalities, or even death. Segmentation of infant brain MRI is particularly challenging when compared with the segmentation of images acquired from older children and adults. We sought to develop a fully automated segmentation strategy and present here a Bayesian approach utilizing an atlas of priors derived from previous segmentations and a new scheme for automatically selecting and iteratively refining classifier training data using the STAPLE algorithm. Results have been validated by comparison to hand-drawn segmentations.
Nain D, Haker S, Bobick A, Tannenbaum A. Shape-driven 3D segmentation using spherical wavelets. Med Image Comput Comput Assist Interv. 2006;9 (Pt 1) :66-74.Abstract
This paper presents a novel active surface segmentation algorithm using a multiscale shape representation and prior. We define a parametric model of a surface using spherical wavelet functions and learn a prior probability distribution over the wavelet coefficients to model shape variations at different scales and spatial locations in a training set. Based on this representation, we derive a parametric active surface evolution using the multiscale prior coefficients as parameters for our optimization procedure to naturally include the prior in the segmentation framework. Additionally, the optimization method can be applied in a coarse-to-fine manner. We apply our algorithm to the segmentation of brain caudate nucleus, of interest in the study of schizophrenia. Our validation shows our algorithm is computationally efficient and outperforms the Active Shape Model algorithm by capturing finer shape details.
Warfield SK, Zou KH, Wells WM. Validation of image segmentation by estimating rater bias and variance. Med Image Comput Comput Assist Interv. 2006;9 (Pt 2) :839-47.Abstract
The accuracy and precision of segmentations of medical images has been difficult to quantify in the absence of a "ground truth" or reference standard segmentation for clinical data. Although physical or digital phantoms can help by providing a reference standard, they do not allow the reproduction of the full range of imaging and anatomical characteristics observed in clinical data. An alternative assessment approach is to compare to segmentations generated by domain experts. Segmentations may be generated by raters who are trained experts or by automated image analysis algorithms. Typically these segmentations differ due to intra-rater and inter-rater variability. The most appropriate way to compare such segmentations has been unclear. We present here a new algorithm to enable the estimation of performance characteristics, and a true labeling, from observations of segmentations of imaging data where segmentation labels may be ordered or continuous measures. This approach may be used with, amongst others, surface, distance transform or level set representations of segmentations, and can be used to assess whether or not a rater consistently over-estimates or under-estimates the position of a boundary.
O'shea JP, Whalen S, Branco DM, Petrovich NM, Knierim KE, Golby AJ. Integrated image- and function-guided surgery in eloquent cortex: a technique report. Int J Med Robot. 2006;2 (1) :75-83.Abstract
The ability to effectively identify eloquent cortex in close proximity to brain tumours is a critical component of surgical planning prior to resection. The use of electrocortical stimulation testing (ECS) during awake neurosurgical procedures remains the gold standard for mapping functional areas, yet the preoperative use of non-invasive brain imaging techniques such as fMRI are gaining popularity as supplemental surgical planning tools. In addition, the intraoperative three-dimensional display of fMRI findings co-registered to structural imaging data maximizes the utility of the preoperative mapping for the surgeon. Advances in these techniques have the potential to limit the size and duration of craniotomies as well as the strain placed on the patient, but more research accurately demonstrating their efficacy is required. In this paper, we demonstrate the integration of preoperative fMRI within a neuronavigation system to aid in surgical planning, as well as the integration of these fMRI data with intraoperative ECS mapping results into a three-dimensional dataset for the purpose of cross-validation.
Hoge SW, Brooks DH. On the complimentarity of SENSE and GRAPPA in parallel MR imaging. Conf Proc IEEE Eng Med Biol Soc. 2006;1 :755-8.Abstract
Two image reconstruction methods currently dominate parallel MR imaging: SENSE and GRAPPA. While both seek to reconstruct images from subsampled multi-channel MRI data, there exist fundamental differences between the two. In particular, SENSE reconstructs an image of the excited spin-density directly whereas GRAPPA reconstructs estimates of the fully sampled raw coil data and then combines them to obtain an image. In this work we show that these differences can be exploited such that each method can compliment the other. In the case of SENSE, which requires an estimate of the coil sensitivity map before reconstruction, one can use GRAPPA to improve the coil sensitivity estimates. Alternatively, using coil sensitivity estimates and the SENSE reconstruction equations, one can improve the GRAPPA reconstruction parameter estimation. Together, these approaches can provide higher image quality than either method alone.
Greenspan M, Wang LI, Ellis R. Validation and improved registration of bone segmentation using contour coherency. Conf Proc IEEE Eng Med Biol Soc. 2006;1 :244-7.Abstract
A method is presented to validate the segmentation of computed tomography (CT) image sequences, and im prove the accuracy and efficiency of the subsequent registration of the 3D surfaces that are reconstructed from the segmented slices. The method compares the shapes of contours extracted from neighborhoods of slices in CT stacks of tibias. The bone is first segmented by an automatic segmentation technique, and the bone contour for each slice is parameterized as a 1-D function of normalized arc length versus inscribed angle. These functions are represented as vectors within a K-dimensional space comprising the first K amplitude coefficients of their Fourier Descriptors. The similarity or coherency of neighboring contours is measured by comparing statistical properties of their vector representations within this space. Experimentation has demonstrated this technique to be very effective at automatically identifying low coherency segmentations, the removal of which significantly improved the accuracy and time efficiency of the registration of 3-D bone surface models.
Mulkern RV, Barnes AS, Haker SJ, Hung YP, Rybicki FJ, Maier SE, Tempany CM. Biexponential characterization of prostate tissue water diffusion decay curves over an extended b-factor range. Magn Reson Imaging. 2006;24 (5) :563-8.Abstract

Detailed measurements of water diffusion within the prostate over an extended b-factor range were performed to assess whether the standard assumption of monoexponential signal decay is appropriate in this organ. From nine men undergoing prostate MR staging examinations at 1.5 T, a single 10-mm-thick axial slice was scanned with a line scan diffusion imaging sequence in which 14 equally spaced b factors from 5 to 3,500 s/mm(2) were sampled along three orthogonal diffusion sensitization directions in 6 min. Due to the combination of long scan time and limited volume coverage associated with the multi-b-factor, multidirectional sampling, the slice was chosen online from the available T2-weighted axial images with the specific goal of enabling the sampling of presumed noncancerous regions of interest (ROIs) within the central gland (CG) and peripheral zone (PZ). Histology from prescan biopsy (n=9) and postsurgical resection (n=4) was subsequently employed to help confirm that the ROIs sampled were noncancerous. The CG ROIs were characterized from the T2-weighted images as primarily mixtures of glandular and stromal benign prostatic hyperplasia, which is prevalent in this population. The water signal decays with b factor from all ROIs were clearly non-monoexponential and better served with bi- vs. monoexponential fits, as tested using chi(2)-based F test analyses. Fits to biexponential decay functions yielded intersubject fast diffusion component fractions in the order of 0.73+/-0.08 for both CG and PZ ROIs, fast diffusion coefficients of 2.68+/-0.39 and 2.52+/-0.38 microm(2)/ms and slow diffusion coefficients of 0.44+/-0.16 and 0.23+/-0.16 um(2)/ms for CG and PZ ROIs, respectively. The difference between the slow diffusion coefficients within CG and PZ was statistically significant as assessed with a Mann-Whitney nonparametric test (P<.05). We conclude that a monoexponential model for water diffusion decay in prostate tissue is inadequate when a large range of b factors is sampled and that biexponential analyses are better suited for characterizing prostate diffusion decay curves.

Sheikov N, McDannold N, Jolesz FA, Zhang Y-Z, Tam K, Hynynen K. Brain Arterioles Show more Active Vesicular Transport of Blood-borne Tracer Molecules than Capillaries and Venules after Focused Ultrasound-evoked Opening of the Blood-brain Barrier. Ultrasound Med Biol. 2006;32 (9) :1399-409.Abstract

Previously, activation of vesicular transport in the brain microvasculature was shown to be one of the mechanisms of focused ultrasound-induced blood-brain barrier (BBB) opening. In the present study, we aimed to estimate the rate of the transendothelial vesicular traffic after focused ultrasound sonication in the rabbit brain, using ultrastructural morphometry and horseradish peroxidase (HRP) as a tracer. In the capillaries, the mean endothelial pinocytotic densities (the number of HRP-containing vesicles per microm(2) of the cell cytoplasm) were 0.9 and 1.05 vesicles/microm(2) 1 h after sonication with ultrasound frequencies of 0.69 and 0.26 MHz, respectively. In the arterioles, these densities were 1.63 and 2.43 vesicles/microm(2), values 1.8 and 2.3 times higher. In control locations, the densities were 0.7 and 0.14 vesicles/microm(2) for capillaries and arterioles, respectively. A small number of HRP-positive vesicles were observed in the venules. Focal delivery of HRP tracer was also observed in light microscopy. The results indicate that the precapillary microvessels play an important role in macromolecular transcytoplasmic traffic through the ultrasound-induced BBB modulation, which should be considered in the future development of trans-BBB drug delivery strategies.

Peled S, Friman O, Jolesz FA, Westin C-F. Geometrically Constrained Two-tensor Model for Crossing Tracts in DWI. Magn Reson Imaging. 2006;24 (9) :1263-70.Abstract

MR diffusion tensor imaging (DTI) of the brain and spine provides a unique tool for both visualizing directionality and assessing intactness of white matter fiber tracts in vivo. At the spatial resolution of clinical MRI, much of primate white matter is composed of interdigitating fibers. Analyses based on an assumed single diffusion tensor per voxel yield important information about the average diffusion in the voxel but fail to reveal structure in the presence of crossing tracts. Until today, all clinical scans assume only one tensor, causing potential serious errors in tractography. Since high angular resolution imaging remains, so far, untenable for routine clinical use, a method is proposed whereby the single-tensor field is augmented with additional information gleaned from standard clinical DTI. The method effectively resolves two distinct tract directions within voxels, in which only two tracts are assumed to exist. The underlying constrained two-tensor model is fitted in two stages, utilizing the information present in the single-tensor fit. As a result, the necessary MRI time can be drastically reduced when compared with other approaches, enabling widespread clinical use. Upon evaluation in simulations and application to in vivo human brain DTI data, the method appears to be robust and practical and, if correctly applied, could elucidate tract directions at critical points of uncertainty.

Dimaio SP, Archip N, Hata N, Talos I-F, Warfield SK, Majumdar A, McDannold N, Hynynen K, Morrison PR, Wells WM, et al. Image-guided Neurosurgery at Brigham and Women’s Hospital. IEEE Eng Med Biol Mag. 2006;25 (5) :67-73.
White PJ, Clement GT, Hynynen K. Local Frequency Dependence in Transcranial Ultrasound Transmission. Phys Med Biol. 2006;51 (9) :2293-305.Abstract

The development of large-aperture multiple-source transducer arrays for ultrasound transmission through the human skull has demonstrated the possibility of controlled and substantial acoustic energy delivery into the brain parenchyma without the necessitation of a craniotomy. The individual control of acoustic parameters from each ultrasound source allows for the correction of distortions arising from transmission through the skull bone and also opens up the possibility for electronic steering of the acoustic focus within the brain. In addition, the capability to adjust the frequency of insonation at different locations on the skull can have an effect on ultrasound transmission. To determine the efficacy and applicability of a multiple-frequency approach with such a device, this study examined the frequency dependence of ultrasound transmission in the range of 0.6-1.4 MHz through a series of 17 points on four ex vivo human skulls. Effects beyond those that are characteristic of frequency-dependent attenuation were examined. Using broadband pulses, it was shown that the reflected spectra from the skull revealed information regarding ultrasound transmission at specific frequencies. A multiple-frequency insonation with optimized frequencies over the entirety of five skull specimens was found to yield on average a temporally brief 230% increase in the transmitted intensity with an 88% decrease in time-averaged intensity transmission within the focal volume. This finding demonstrates a potential applicability of a multiple-frequency approach in transcranial ultrasound transmission.

Talos I-F, Mian AZ, Zou KH, Hsu L, Goldberg-Zimring D, Haker S, Bhagwat JG, Mulkern RV. Magnetic Resonance and the Human Brain: Anatomy, Function and Metabolism. Cell Mol Life Sci. 2006;63 (10) :1106-24.Abstract

The introduction and development, over the last three decades, of magnetic resonance (MR) imaging and MR spectroscopy technology for in vivo studies of the human brain represents a truly remarkable achievement, with enormous scientific and clinical ramifications. These effectively non-invasive techniques allow for studies of the anatomy, the function and the metabolism of the living human brain. They have allowed for new understandings of how the healthy brain works and have provided insights into the mechanisms underlying multiple disease processes which affect the brain. Different MR techniques have been developed for studying anatomy, function and metabolism. The primary focus of this review is to describe these different methodologies and to briefly review how they are being employed to more fully appreciate the intricacies associated with the organ, which most distinctly differentiates the human species from the other animal forms on earth.

McDannold N, Hynynen K. Quality Assurance and System Stability of a Clinical MRI-guided Focused Ultrasound System: Four-year Experience. Med Phys. 2006;33 (11) :4307-13.Abstract

To retrospectively evaluate the four-year experience of a quality assurance method for a MRI-guided focused ultrasound system that uses temperature maps acquired during heating in an ultrasound/MRI phantom. This quality assurance method was performed before 148 clinical uterine fibroid thermal ablation treatments. The stability of the peak temperature rise, the targeting accuracy, the shape of the heated zone, and the noise level in the imaging was evaluated. The peak temperature rise was mostly stable for the first three years. An increase in heating was observed when the system was replaced after year three. Detection of this increase was taken into account in the subsequent clinical treatments. A small secondary hotspot was detected by the temperature maps and was seen to be resolved after system calibration. The average standard deviation in unheated regions of the phantom in the temperature maps was 0.5 +/- 0.2 degrees C; it was less than 1 degrees C in all but one procedure. The average initial targeting error was 2.8 +/- 1.8 and 2.8 +/- 2.1 mm in two radial directions and 7.7 +/- 2.9 mm along the ultrasound beam direction. The width of the heating profile was consistent over the four years. This simple method to evaluate the performance appeared to be sensitive to small changes in system performance, which was adequately stable over a four-year time period.

2005
Haker S, Wells WM, Warfield SK, Talos I-F, Bhagwat JG, Goldberg-Zimring D, Mian A, Ohno-Machado L, Zou KH. Combining Classifiers using their Receiver Operating Characteristics and Maximum Likelihood Estimation. Med Image Comput Comput Assist Interv. 2005;8 (Pt 1) :506-14.Abstract

In any medical domain, it is common to have more than one test (classifier) to diagnose a disease. In image analysis, for example, there is often more than one reader or more than one algorithm applied to a certain data set. Combining of classifiers is often helpful, but determining the way in which classifiers should be combined is not trivial. Standard strategies are based on learning classifier combination functions from data. We describe a simple strategy to combine results from classifiers that have not been applied to a common data set, and therefore can not undergo this type of joint training. The strategy, which assumes conditional independence of classifiers, is based on the calculation of a combined Receiver Operating Characteristic (ROC) curve, using maximum likelihood analysis to determine a combination rule for each ROC operating point. We offer some insights into the use of ROC analysis in the field of medical imaging.

Yang Y, Zhu L, Haker S, Tannenbaum AR, Giddens DP. Harmonic Skeleton Guided Evaluation of Stenoses in Human Coronary Arteries. Med Image Comput Comput Assist Interv. 2005;8 (Pt 1) :490-7.Abstract

This paper presents a novel approach that three-dimensionally visualizes and evaluates stenoses in human coronary arteries by using harmonic skeletons. A harmonic skeleton is the center line of a multi-branched tubular surface extracted based on a harmonic function, which is the solution of the Laplace equation. This skeletonization method guarantees smoothness and connectivity and provides a fast and straightforward way to calculate local cross-sectional areas of the arteries, and thus provides the possibility to localize and evaluate coronary artery stenosis, which is a commonly seen pathology in coronary artery disease.

Haker SJ, Mulkern RV, Roebuck JR, Barnes AS, DiMaio S, Hata N, Tempany CM. Magnetic Resonance Guided Prostate Interventions. Top Magn Reson Imaging. 2005;16 (5) :355-68.Abstract

We review our experience using an open 0.5-T magnetic resonance (MR) interventional unit to guide procedures in the prostate. This system allows access to the patient and real-time MR imaging simultaneously and has made it possible to perform prostate biopsy and brachytherapy under MR guidance. We review MR imaging of the prostate and its use in targeted therapy, and describe our use of image processing methods such as image registration to further facilitate precise targeting. We describe current developments with a robot assist system being developed to aid radioactive seed placement.

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