Publications

2014
Wachinger C, Golland P, Reuter M, Wells III WM. Gaussian Process Interpolation for Uncertainty Estimation in Image Registration. Med Image Comput Comput Assist Interv. 2014;17 (Pt 1) :267-74.Abstract

Intensity-based image registration requires resampling images on a common grid to evaluate the similarity function. The uncertainty of interpolation varies across the image, depending on the location of resampled points relative to the base grid. We propose to perform Bayesian inference with Gaussian processes, where the covariance matrix of the Gaussian process posterior distribution estimates the uncertainty in interpolation. The Gaussian process replaces a single image with a distribution over images that we integrate into a generative model for registration. Marginalization over resampled images leads to a new similarity measure that includes the uncertainty of the interpolation. We demonstrate that our approach increases the registration accuracy and propose an efficient approximation scheme that enables seamless integration with existing registration methods.

Santagata S, Eberlin LS, Norton I, Calligaris D, Feldman DR, Ide JL, Liu X, Wiley JS, Vestal ML, Ramkissoon SH, et al. Intraoperative Mass Spectrometry Mapping of an Onco-metabolite to Guide Brain Tumor Surgery. Proc Natl Acad Sci U S A. 2014;111 (30) :11121-6.Abstract

For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI MS, we identify isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity within minutes, immediately providing critical diagnostic, prognostic, and predictive information. Imaging tissue sections with DESI MS shows that the 2-HG signal overlaps with areas of tumor and that 2-HG levels correlate with tumor content, thereby indicating tumor margins. Mapping the 2-HG signal onto 3D MRI reconstructions of tumors allows the integration of molecular and radiologic information for enhanced clinical decision making. We also validate the methodology and its deployment in the operating room: We have installed a mass spectrometer in our Advanced Multimodality Image Guided Operating (AMIGO) suite and demonstrate the molecular analysis of surgical tissue during brain surgery. This work indicates that metabolite-imaging MS could transform many aspects of surgical care.

Gregory ST, Schmidt EJ, Zhang SH, Kwong RY, Stevenson WG, Murrow JR, Tse ZTH. Left-ventricular Mechanical Activation and Aortic-arch Orientation Recovered from Magneto-hydrodynamic Voltages Observed in 12-lead ECGs Obtained Inside MRIs: A Feasibility Study. Ann Biomed Eng. 2014;42 (12) :2480-9.Abstract

To explore use of the Magnetohydrodynamic Voltage (VMHD), observed in intra-MRI 12-lead electrocardiograms (ECG), to indicate the timing of the onset of left-ventricular mechanical activation (LVMA) and the orientation of the aortic-arch (AAO). Blood flow through the aortic arch during systole, in the presence of the MRI magnetic field (B 0), generates VMHD. Since the magnitude and direction of VMHD are determined by the timing and directionality of blood flow relative to B 0, we hypothesized that clinically useful measures, LVMA and AAO, could be extracted from temporal and vectorial VMHD characteristics. VMHD signals were extracted from 12-lead ECG traces by comparing traces obtained inside and outside the MRI scanner. VMHD was converted into the Vectorcardiogram frame of reference. LVMA was quantified in 1 subject at 1.5T and 3 subjects at 3T, and the result compared to CINE MRI. AAO was inferred for 4 subjects at 3T and compared to anatomical imaging of the aortic arch orientation in the transverse plane. A < 10% error was observed in LVMA measurements, while a < 3° error was observed in aortic arch orientation measurements. The temporal and vectorial nature of VMHD is useful in estimating these clinically relevant parameters.

Glykys J, Dzhala V, Egawa K, Balena T, Saponjian Y, Kuchibhotla KV, Bacskai BJ, Kahle KT, Zeuthen T, Staley KJ. Local Impermeant Anions Establish the Neuronal Chloride Concentration. Science. 2014;343 (6171) :670-5.Abstract

Neuronal intracellular chloride concentration [Cl(-)](i) is an important determinant of γ-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl(-) across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl(-)](i). Measurement of [Cl(-)](i) in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A](i)) and polyanionic extracellular matrix glycoproteins ([A](o)) constrain the local [Cl(-)]. CCC inhibition had modest effects on [Cl(-)](i) and neuronal volume, but substantial changes were produced by alterations of the balance between [A](i) and [A](o). Therefore, CCCs are important elements of Cl(-) homeostasis, but local impermeant anions determine the homeostatic set point for [Cl(-)], and hence, neuronal volume and the polarity of local GABA(A)R signaling.

Jolesz FA, McDannold NJ. Magnetic Resonance-guided Focused Ultrasound: A New Technology for Clinical Neurosciences. Neurol Clin. 2014;32 (1) :253-69.Abstract

Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an old idea but a new technology that may change the entire clinical field of the neurosciences. TcMRgFUS has no cumulative effect, and it is applicable for repeatable treatments, controlled by real-time dosimetry, and capable of immediate tissue destruction. Most importantly, it has extremely accurate targeting and constant monitoring. It is potentially more precise than proton beam therapy and definitely more cost effective. Neuro-oncology may be the most promising area of future TcMRgFUS applications.

Garlapati RR, Roy A, Joldes GR, Wittek A, Mostayed A, Doyle B, Warfield SK, Kikinis R, Knuckey N, Bunt S, et al. More Accurate Neuronavigation Data Provided by Biomechanical Modeling Instead of Rigid Registration. J Neurosurg. 2014;120 (6) :1477-83.Abstract

It is possible to improve neuronavigation during image-guided surgery by warping the high-quality preoperative brain images so that they correspond with the current intraoperative configuration of the brain. In this paper, the accuracy of registration results obtained using comprehensive biomechanical models is compared with the accuracy of rigid registration, the technology currently available to patients. This comparison allows investigation into whether biomechanical modeling provides good-quality image data for neuronavigation for a larger proportion of patients than rigid registration. Preoperative images for 33 neurosurgery cases were warped onto their respective intraoperative configurations using both the biomechanics-based method and rigid registration. The Hausdorff distance-based evaluation process, which measures the difference between images, was used to quantify the performance of both registration methods. A statistical test for difference in proportions was conducted to evaluate the null hypothesis that the proportion of patients for whom improved neuronavigation can be achieved is the same for rigid and biomechanics-based registration. The null hypothesis was confidently rejected (p < 10(-4)). Even the modified hypothesis that fewer than 25% of patients would benefit from the use of biomechanics-based registration was rejected at a significance level of 5% (p = 0.02). The biomechanics-based method proved particularly effective in cases demonstrating large craniotomy-induced brain deformations. The outcome of this analysis suggests that nonlinear biomechanics-based methods are beneficial to a large proportion of patients and can be considered for use in the operating theater as a possible means of improving neuronavigation and surgical outcomes.

Chen Y, Kwok K-W, Tse ZTH. An MR-conditional High-torque Pneumatic Stepper Motor for MRI-guided and Robot-assisted Intervention. Ann Biomed Eng. 2014;42 (9) :1823-33.Abstract

Magnetic resonance imaging allows for visualizing detailed pathological and morphological changes of soft tissue. MR-conditional actuations have been widely investigated for development of image-guided and robot-assisted surgical devices under the Magnetic resonance imaging (MRI). This paper presents a simple design of MR-conditional stepper motor which can provide precise and high-torque actuation without adversely affecting the MR image quality. This stepper motor consists of two MR-conditional pneumatic cylinders and the corresponding supporting structures. Alternating the pressurized air can drive the motor to rotate each step in 3.6° with the motor coupled to a planetary gearbox. Experimental studies were conducted to validate its dynamics performance. Maximum 800 mN m output torque is achieved. The motor accuracy independently varied by two factors: motor operating speed and step size, was also investigated. The motor was tested within a 3T Siemens MRI scanner (MAGNETOM Skyra, Siemens Medical Solutions, Erlangen, Germany) and a 3T GE MRI scanner (GE SignaHDx, GE Healthcare, Milwaukee, WI, USA). The image artifact and the signal-to-noise ratio (SNR) were evaluated for study of its MRI compliancy. The results show that the presented pneumatic stepper motor generated 2.35% SNR reduction in MR images. No observable artifact was presented besides the motor body itself. The proposed motor test also demonstrates a standard to evaluate the pneumatic motor capability for later incorporation with motorized devices used under MRI.

Paltiel HJ, Estrada CR, Alomari AI, Stamoulis C, Passerotti CC, Meral CF, Lee RS, Clement GT. Multi-planar Dynamic Contrast-Enhanced Ultrasound Assessment of Blood Flow in a Rabbit Model of Testicular Torsion. Ultrasound Med Biol. 2014;40 (2) :361-70.Abstract

To assess correlation between multi-planar, dynamic contrast-enhanced ultrasound (US) blood flow measurements and radiolabeled microsphere blood flow measurements, five groups of six rabbits underwent unilateral testicular torsion of 0°, 180°, 360°, 540° or 720°. Five US measurements per testis (three transverse/two longitudinal) were obtained pre-operatively and immediately and 4 and 8 h post-operatively using linear transducers (7-4 MHz/center frequency 4.5 MHz/10 rabbits; 9-3 MHz/center frequency 5.5 MHz/20 rabbits). Björck's linear least-squares method fit the rise phase of mean pixel intensity over a 7-s period for each time curve. Slope of fit and intervention/control US pixel intensity ratios were calculated. Means of transverse, longitudinal and combined transverse/longitudinal US ratios as a function of torsion degree were compared with radiolabeled microsphere ratios using Pearson's correlation coefficient, ρ. There was high correlation between the two sets of ratios (ρ ≥ 0.88, p ≤ 0.05), except for the transverse US ratio in the immediate post-operative period (ρ = 0.79, p = 0.11). These results hold promise for future clinical applications.

Crabb MG, Davidson JL, Little R, Wright P, Morgan AR, Miller CA, Naish JH, Parker GJM, Kikinis R, McCann H, et al. Mutual Information as a Measure of Image Quality for 3-D Dynamic Lung Imaging with EIT. Physiol Meas. 2014;35 (5) :863-79.Abstract

We report on a pilot study of dynamic lung electrical impedance tomography (EIT) at the University of Manchester. Low-noise EIT data at 100 frames per second were obtained from healthy male subjects during controlled breathing, followed by magnetic resonance imaging (MRI) subsequently used for spatial validation of the EIT reconstruction. The torso surface in the MR image and electrode positions obtained using MRI fiducial markers informed the construction of a 3D finite element model extruded along the caudal-distal axis of the subject. Small changes in the boundary that occur during respiration were accounted for by incorporating the sensitivity with respect to boundary shape into a robust temporal difference reconstruction algorithm. EIT and MRI images were co-registered using the open source medical imaging software, 3D Slicer. A quantitative comparison of quality of different EIT reconstructions was achieved through calculation of the mutual information with a lung-segmented MR image. EIT reconstructions using a linear shape correction algorithm reduced boundary image artefacts, yielding better contrast of the lungs, and had 10% greater mutual information compared with a standard linear EIT reconstruction.

Schmidt EJ, Fung MM, Ciris PA, Song T, Shankaranarayanan A, Holmvang G, Gupta SN, Chaput M, Levine RA, Ruskin J, et al. Navigated DENSE Strain Imaging for Post-radiofrequency Ablation Lesion Assessment in the Swine Left Atria. Europace. 2014;16 (1) :133-41.Abstract

AIMS: Prior work has demonstrated that magnetic resonance imaging (MRI) strain can separate necrotic/stunned myocardium from healthy myocardium in the left ventricle (LV). We surmised that high-resolution MRI strain, using navigator-echo-triggered DENSE, could differentiate radiofrequency ablated tissue around the pulmonary vein (PV) from tissue that had not been damaged by radiofrequency energy, similarly to navigated 3D myocardial delayed enhancement (3D-MDE). METHODS AND RESULTS: A respiratory-navigated 2D-DENSE sequence was developed, providing strain encoding in two spatial directions with 1.2 × 1.0 × 4 mm(3) resolution. It was tested in the LV of infarcted sheep. In four swine, incomplete circumferential lesions were created around the right superior pulmonary vein (RSPV) using ablation catheters, recorded with electro-anatomic mapping, and imaged 1 h later using atrial-diastolic DENSE and 3D-MDE at the left atrium/RSPV junction. DENSE detected ablation gaps (regions with >12% strain) in similar positions to 3D-MDE (2D cross-correlation 0.89 ± 0.05). Low-strain (<8%) areas were, on average, 33% larger than equivalent MDE regions, so they include both injured and necrotic regions. Optimal DENSE orientation was perpendicular to the PV trunk, with high shear strain in adjacent viable tissue appearing as a sensitive marker of ablation lesions. CONCLUSIONS: Magnetic resonance imaging strain may be a non-contrast alternative to 3D-MDE in intra-procedural monitoring of atrial ablation lesions.

Yoshimitsu K, Kato T, Song S-E, Hata N. A Novel Four-wire-driven Robotic Catheter for Radio-frequency Ablation Treatment. Int J Comput Assist Radiol Surg. 2014;9 (5) :867-74.Abstract

PURPOSE:    Robotic catheters have been proposed to increase the efficacy and safety of the radio-frequency ablation treatment. The robotized motion of current robotic catheters mimics the motion of manual ones-namely, deflection in one direction and rotation around the catheter. With the expectation that the higher dexterity may achieve further efficacy and safety of the robotically driven treatment, we prototyped a four-wire-driven robotic catheter with the ability to deflect in two- degree-of-freedom motions in addition to rotation. METHODS:    A novel quad-directional structure with two wires was designed and developed to attain yaw and pitch motion in the robotic catheter. We performed a mechanical evaluation of the bendability and maneuverability of the robotic catheter and compared it with current manual catheters. RESULTS:    We found that the four-wire-driven robotic catheter can achieve a pitching angle of 184.7[Formula: see text] at a pulling distance of wire for 11 mm, while the yawing angle was 170.4[Formula: see text] at 11 mm. The robotic catheter could attain the simultaneous two- degree-of-freedom motions in a simulated cardiac chamber. CONCLUSION:    The results indicate that the four-wire-driven robotic catheter may offer physicians the opportunity to intuitively control a catheter and smoothly approach the focus position that they aim to ablate.

Golshan M, Sagara Y, Wexelman B, Aydogan F, Desantis S, Elise Min H, Vosburgh K, Jagadeesan J, Caragacianu D, Gombos E, et al. Pilot Study to Evaluate Feasibility of Image-Guided Breast-Conserving Therapy in the Advanced Multimodal Image-Guided Operating (AMIGO) Suite. Ann Surg Oncol. 2014;21 (10) :3356-7.Abstract

BACKGROUND: The rate of reexcision in breast-conserving surgery remains high, leading to delay in initiation of adjuvant therapy, increased cost, increased complications, and negative psychological impact to the patient.1 (-) 3 We initiated a phase 1 clinical trial to determine the feasibility of the use of intraoperative magnetic resonance imaging (MRI) to assess margins in the advanced multimodal image-guided operating (AMIGO) suite. METHODS: All patients received contrast-enhanced three-dimensional MRI while under general anesthesia in the supine position, followed by standard BCT with or without wire guidance and sentinel node biopsy. Additional margin reexcision was performed of suspicious margins and correlated to final pathology (Fig. 1). Feasibility was assessed via two components: demonstration of safety and sterility and acceptable duration of the operation and imaging; and adequacy of intraoperative MRI imaging for interpretation and its comparison to final pathology. Fig. 1 Schema of AMIGO trial RESULTS: Eight patients (mean age 48.5 years), 4 with stage I breast cancer and 4 with stage II breast cancer, were recruited. All patients underwent successful BCT in the AMIGO suite with no AMIGO-specific complications or break in sterility during surgery. The mean operative time was 113 min (range 93-146 min). CONCLUSIONS: Our experience with AMIGO suggests that it is feasible to use intraoperative MRI imaging to evaluate margin assessment in real time. Further research is required to identify modalities that will lead to a reduction in reexcision in breast cancer therapy.

Penzkofer T, Tempany CM. Prostate Cancer Detection and Diagnosis: The Role of MR and its Comparison with Other Diagnostic Modalities - A Radiologist's Perspective. NMR Biomed. 2014;27 (1) :3-15.Abstract

It is now universally recognized that many prostate cancers are over-diagnosed and over-treated. The European Randomized Study of Screening for Prostate Cancer from 2009 evidenced that, to save one man from death from prostate cancer, over 1400 men need to be screened, and 48 need to undergo treatment. The detection of prostate cancer is traditionally based on digital rectal examination (DRE) and the measurement of serum prostate-specific antigen (PSA), followed by ultrasound-guided biopsy. The primary role of imaging for the detection and diagnosis of prostate cancer has been transrectal ultrasound (TRUS) guidance during biopsy. Traditionally, MRI has been used primarily for the staging of disease in men with biopsy-proven cancer. It has a well-established role in the detection of T3 disease, planning of radiation therapy, especially three-dimensional conformal or intensity-modulated external beam radiation therapy, and planning and guiding of interstitial seed implant or brachytherapy. New advances have now established that prostate MRI can accurately characterize focal lesions within the gland, an ability that has led to new opportunities for improved cancer detection and guidance for biopsy. Two new approaches to prostate biopsy are under investigation. Both use pre-biopsy MRI to define potential targets for sampling, and the biopsy is performed either with direct real-time MR guidance (in-bore) or MR fusion/registration with TRUS images (out-of-bore). In-bore and out-of-bore MRI-guided prostate biopsies have the advantage of using the MR target definition for the accurate localization and sampling of targets or suspicious lesions. The out-of-bore method uses combined MRI/TRUS with fusion software that provides target localization and increases the sampling accuracy of TRUS-guided biopsies by integrating prostate MRI information with TRUS. Newer parameters for each imaging modality, such as sonoelastography or shear wave elastography, contrast-enhanced ultrasound and MRI elastography, show promise to further enrich datasets.

Fedorov A, Song S-E, Kapur T, Owen R, Sugar EN, Nguyen P, Wells III WM, Tempany CM. Prototype Design and Phantom Evaluation of a Device for Co-registered MRI/TRUS Imaging of the Prostate. Clin Image Based Proced. 2014;8361 :125-33.Abstract

Magnetic Resonance Imaging (MRI) and transrectal Ultrasound (TRUS) are both used in imaging interventions in men suspected of having and with prostate cancer for diagnosis as well as treatment. Due to the widespread availability and ease of use of TRUS, it is widely acknowledged that availability of spatially registered MRI/TRUS data could provide the optimal combination for characterization of prostate tissue and interventional guidance. To provide such spatially aligned data, we propose a device to support co-registered acquisition of MRI and TRUS data while maintaining a stable configuration (shape) of the prostate. We present the design and evaluation of a custom sleeve that can be introduced transrectally, and can accommodate both TRUS and endorectal MRI probes. Our experiments on a phantom have demonstrated that imaging with this sleeve did not compromise differentiation of internal structures and did not affect the quality of the MR acquisition. Reduction of the signal and contrast were however observed and quantified in the TRUS data. Further evaluation and modification of the device necessary for possible patient studies are discussed.

Gill G, Toews M, Beichel R. Robust Initialization of Active Shape Models for Lung Segmentation in CT Scans: A Feature-Based Atlas Approach. Int J Biomed Imaging. 2014;2014 :479154.Abstract

Model-based segmentation methods have the advantage of incorporating a priori shape information into the segmentation process but suffer from the drawback that the model must be initialized sufficiently close to the target. We propose a novel approach for initializing an active shape model (ASM) and apply it to 3D lung segmentation in CT scans. Our method constructs an atlas consisting of a set of representative lung features and an average lung shape. The ASM pose parameters are found by transforming the average lung shape based on an affine transform computed from matching features between the new image and representative lung features. Our evaluation on a diverse set of 190 images showed an average dice coefficient of 0.746 ± 0.068 for initialization and 0.974 ± 0.017 for subsequent segmentation, based on an independent reference standard. The mean absolute surface distance error was 0.948 ± 1.537 mm. The initialization as well as segmentation results showed a statistically significant improvement compared to four other approaches. The proposed initialization method can be generalized to other applications employing ASM-based segmentation.

Horky LL, Gerbaudo VH, Zaitsev A, Plesniak W, Hainer J, Govindarajulu U, Kikinis R, Dietrich J. Systemic Chemotherapy Decreases Brain Glucose Metabolism. Ann Clin Transl Neurol. 2014;1 (10) :788-98.Abstract

OBJECTIVE: Cancer patients may experience neurologic adverse effects, such as alterations in neurocognitive function, as a consequence of chemotherapy. The mechanisms underlying such neurotoxic syndromes remain poorly understood. We here describe the temporal and regional effects of systemically administered platinum-based chemotherapy on glucose metabolism in the brain of cancer patients. METHODS: Using sequential FDG-PET/CT imaging prior to and after administration of chemotherapy, we retrospectively characterized the effects of intravenously administered chemotherapy on brain glucose metabolism in a total of 24 brain regions in a homogenous cohort of 10 patients with newly diagnosed non-small-cell lung cancer. RESULTS: Significant alterations of glucose metabolism were found in response to chemotherapy in all gray matter structures, including cortical structures, deep nuclei, hippocampi, and cerebellum. Metabolic changes were also notable in frontotemporal white matter (WM) network systems, including the corpus callosum, subcortical, and periventricular WM tracts. INTERPRETATION: Our data demonstrate a decrease in glucose metabolism in both gray and white matter structures associated with chemotherapy. Among the affected regions are those relevant to the maintenance of brain plasticity and global neurologic function. This study potentially offers novel insights into the spatial and temporal effects of systemic chemotherapy on brain metabolism in cancer patients.

Ren H, Campos-Nanez E, Yaniv Z, Banovac F, Abeledo H, Hata N, Cleary K. Treatment Planning and Image Guidance for Radiofrequency Ablations of Large Tumors. IEEE J Biomed Health Inform. 2014;18 (3) :920-8.Abstract

This article addresses the two key challenges in computer-assisted percutaneous tumor ablation: planning multiple overlapping ablations for large tumors while avoiding critical structures, and executing the prescribed plan. Toward semiautomatic treatment planning for image-guided surgical interventions, we develop a systematic approach to the needle-based ablation placement task, ranging from preoperative planning algorithms to an intraoperative execution platform. The planning system incorporates clinical constraints on ablations and trajectories using a multiple objective optimization formulation, which consists of optimal path selection and ablation coverage optimization based on integer programming. The system implementation is presented and validated in both phantom and animal studies. The presented system can potentially be further extended for other ablation techniques such as cryotherapy.

Lee JW, Norden AD, Ligon KL, Golby AJ, Beroukhim R, Quackenbush J, Wells W, Oelschlager K, Maetzold D, Wen PY. Tumor Associated Seizures in Glioblastomas are Influenced by Survival Gene Expression in a Region-specific Manner: A Gene Expression Imaging Study. Epilepsy Res. 2014;108 (5) :843-52.Abstract

Tumor associated seizures (TAS) are common and cause significant morbidity. Both imaging and gene expression features play significant roles in determining TAS, with strong interactions between them. We describe gene expression imaging tools which allow mapping of brain regions where gene expression has significant influence on TAS, and apply these methods to study 77 patients who underwent surgical evaluation for supratentorial glioblastomas. Tumor size and location were measured from MRI scans. A 9-set gene expression profile predicting long-term survivors was obtained from RNA derived from formalin-fixed paraffin embedded tissue. A total of 32 patients (42%) experienced preoperative TAS. Tumor volume was smaller (31.1 vs. 58.8 cubic cm, p<0.001) and there was a trend toward median survival being higher (48.4 vs. 32.7 months, p=0.055) in patients with TAS. Although the expression of only OLIG2 was significantly lower in patients with TAS in a groupwise analysis, gene expression imaging analysis revealed regions with significantly lower expression of OLIG2 and RTN1 in patients with TAS. Gene expression imaging is a powerful technique that demonstrates that the influence of gene expression on TAS is highly region specific. Regional variability should be evaluated with any genomic or molecular markers of solid brain lesions.

Aryal M, Arvanitis CD, Alexander PM, McDannold N. Ultrasound-Mediated Blood-brain Barrier Disruption for Targeted Drug Delivery in the Central Nervous System. Adv Drug Deliv Rev. 2014;72 :94-109.Abstract

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB.

Schmidt EJ, Tse ZTH, Reichlin TR, Michaud GF, Watkins RD, Butts-Pauly K, Kwong RY, Stevenson W, Schweitzer J, Byrd I, et al. Voltage-based Device Tracking in a 1.5 Tesla MRI during Imaging: Initial Validation in Swine Models. Magn Reson Med. 2014;71 (3) :1197-209.Abstract

PURPOSE: Voltage-based device-tracking (VDT) systems are commonly used for tracking invasive devices in electrophysiological cardiac-arrhythmia therapy. During electrophysiological procedures, electro-anatomic mapping workstations provide guidance by integrating VDT location and intracardiac electrocardiogram information with X-ray, computerized tomography, ultrasound, and MR images. MR assists navigation, mapping, and radiofrequency ablation. Multimodality interventions require multiple patient transfers between an MRI and the X-ray/ultrasound electrophysiological suite, increasing the likelihood of patient-motion and image misregistration. An MRI-compatible VDT system may increase efficiency, as there is currently no single method to track devices both inside and outside the MRI scanner. METHODS: An MRI-compatible VDT system was constructed by modifying a commercial system. Hardware was added to reduce MRI gradient-ramp and radiofrequency unblanking pulse interference. VDT patches and cables were modified to reduce heating. Five swine cardiac VDT electro-anatomic mapping interventions were performed, navigating inside and thereafter outside the MRI. RESULTS: Three-catheter VDT interventions were performed at >12 frames per second both inside and outside the MRI scanner with <3 mm error. Catheters were followed on VDT- and MRI-derived maps. Simultaneous VDT and imaging was possible in repetition time >32 ms sequences with <0.5 mm errors, and <5% MRI signal-to-noise ratio (SNR) loss. At shorter repetition times, only intracardiac electrocardiogram was reliable. Radiofrequency heating was <1.5°C. CONCLUSION: An MRI-compatible VDT system is feasible.

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