John Pauly - US grants

DESCRIPTION (Adapted from Applicant's Abstract): This application is a competing renewal. The original project concerned new fast magnetic resonance imaging (MRI) techniques for improved diagnosis of abdominal tumors. Significant progress was made in developing several fast-scan methods that produce high-quality T2-weighted abdominal images in a breath-hold. The focus of this competing renewal is on new MR methods that take the next step beyond tumor detection---the guidance of tumor biopsies and other interventional procedures using MR. The project title has been modified to reflect this change in focus. The aims of this project are to 1) design and implement a real-time, interactive (RTI) MRI system tailored for interventional procedures, 2) develop and integrate into the RTI system new sequences that provide useful image contrast for interventional procedures; and 3) evaluate this new MR interventional system on phantoms and patients. The research plan includes substantial technical development of a versatile RTI MRI platform, studies of improved MR acquisition methods (e.g., steady-state free precession, fast spin echo, and color flow), and systematic tests to validate the performance of the resultant system. A research team with extensive technical and clinical expertise has been assembled for this project. This expertise, along with the state-of-the-art scanners available, make Stanford University an ideal environment to carry out this project.

DESCRIPTION (provided by applicant): Functional Magnetic Resonance Imaging (fMRI) has revolutionized neuroscience by mapping activity throughout the brain without the use of radioactive tracers, electrical probes or other invasive procedures. The dominant method for fMRI, Blood Oxygenation Level Dependent (BOLD) imaging, is sensitive to changes in blood oxygenation that occur in response to brain activity. While BOLD imaging represents a major advance in brain mapping, this method has a number of significant limitations including poor spatial resolution, low signal levels, limited contrast and severe image artifacts. These limitations derive from the fact that BOLD contrast is slow to develop, resulting in a loss of signal and a sensitivity to image artifacts. Our group has developed a new steady-state fMRI method that has the potential to overcome these limitations by sensing changes in blood oxygenation more directly. The steady-state signal can be made intrinsically sensitive to oxygenation, allowing data to be gathered under significantly better imaging conditions. Steady-state fMRI is expected to produce artifact-free images with high spatial resolution, and provide high signal levels with excellent functional contrast. The work described in this proposal will take the first steps in transforming this nascent method into a practical tool for neuroscience experiments. Development of the imaging methodology will be accompanied by analysis of the spatial and temporal characteristics of the functional signal, as well as comparison with standard BOLD imaging. This proposal will focus on the visual system as a well-characterized testbed of widespread interest in the neuroscience community. Development will be guided by the specific goals of spatial and temporal characterization in the visual cortex.

chronic obstructive pulmonary disease; functional /structural genomics; racial /ethnic difference

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The goal of this proposal is to develop and validate a comprehensive examination of valvular heart diseases. Valvular heart disease affects approximately 10% of the general population in the United States. Over the past 20 years, valvular diagnosis has undergone a revolution due to advances in cardiac ultrasound. However, ultrasound has inherent limitations with respect to tissue characterization, spatial resolution, and the need for acoustic windows. Particularly difficult are the evaluation of valvular morphology, quantitation of valvular stenosis and identification and quantitation of valvular regurgitation. The examination of valvular heart disease includes the assessment of valvular morphology, cardiac output, intracardiac pressures, ventricular volume and volume regurgitations. Magnetic resonance imaging (MRI) is potentially the most appropriate technique for addressing all of these areas in a single examination. Current MR techniques for valvular imaging suffer from poor temporal and spatial resolutions, require prolonged acquisitions, and frequently require laborious post processing. As a result, there is a gap between what is scientifically feasible and what is currently applied clinically. Our goal in this proposal is to eliminate this gap between the potential of MRI and current clinical practice. Our group has pioneered many of the components that will be useful for the diagnosis of valvular heart disease, including real-time imaging, real-time color flow, and MR Doppler. In this proposal we will integrate and extend these components along with new developments to provide an integrated and comprehensive assessment of valvular function. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Minimally-invasive catheter-based interventions have revolutionized our treatment of cardiovascular disease. X-ray techniques have been the established method for imaging coronary and vascular disease and guiding interventional therapeutic devices. X-ray, however, does not directly visualize the diseased atherosclerotic tissue, limiting more advanced vascular interventions. Magnetic resonance imaging (MRI), by comparison, provides excellent tissue contrast and can image both the vessel lumen and the vessel wall without relying on contrast agents. At Stanford we have been actively developing real-time interactive MR imaging systems for diagnostic cardiac imaging, and for the guidance of interventional procedures. In this proposal we will significantly extend this work to the visualization and control of devices for vascular interventions, and the integration of these capabilities into a multi-functional interactive real-time interface. The major focus will be to develop a fully integrated MRI system for real-time vascular interventions and to optimize its capabilities in animal models for the treatment of chronic total occlusions.

[unreadable] DESCRIPTION (provided by applicant): Radiofrequency ablation (RFA) is emerging as an effective image-guided minimally invasive therapeutic alternative to surgical treatment of cancer tumors. RFA appears well suited to nonresectable tumors in liver. The ablation process is highly dependent on the electrical conductivity of these tissues yet there is no easy way to predict the current pathways or how focused the current will be on the tumor. For example, bone and fatty pockets can shield tumor from ablation currents. Our goal is to enhance the planning and efficacy of tumor ablation by using an MRI system that can map RF ablation current pathways during ablation and map thermal changes. RF current maps will show where power is being deposited, and MR thermometry will show where heat flowed during the ablation. Our approach exploits a new MRI technique that images RF current density in tissue. The ablation electrode is injected with RF currents at the resonant frequency of the MRI scanner. The MRI scanner can directly image the intense magnetic fields associated with the ablation current, and then derive the map of current flow in tissue. In our preliminary work, we have already visualized the current flow in an MR compatible ablation electrode. These tests demonstrated that fatty tissue effectively insulates and blocks the ablation current. Moreover, the current pathway itself lights up high conductivity tissue and creates a medically significant contrast. To fully exploit this capability, we will merge RF current mapping with MR thermometry and ablation devices to form a comprehensive interventional MRI system for RF ablation. Enhanced RF hardware, pulse sequences and reconstructions will be developed. Upon completion, we will perform ex-vivo tissue sample and in-vivo animal studies to demonstrate the clinical potential of this system. If we achieve these goals, MR guided ablation imaging and thermal monitoring should enable better treatment planning for the ablation, and provide improved time and spatial monitoring as tumor ablation progresses. MR guided RF ablation gives the patient an effective option for a minimally invasive treatment of cancer tumors and a more controllable therapy. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Functional magnetic resonance imaging (fMRI) has revolutionized the neurosciences by providing noninvasive tools for monitoring changes in blood oxygenation or tissue perfusion associated with brain activation. The most common approach is blood oxygenation dependent (BOLD) imaging. Unfortunately, the MRI acquisition parameters that provide the oxygen sensitivity in BOLD also produce sensitivity to image artifacts, signal dropouts, and spatial distortion. The aim of this proposal is to develop alternatives to BOLD without these limitations. The new methods described in this proposal are based on oxygen-dependent signal changes in rapid, short TR, fully refocused imaging acquisition techniques, known as steady-state free precession, or SSFP. These approaches exploit the changes in the steady-state signal due to oxygenation changes. Once this steady-state oxygenation dependent contrast has been established, it can be captured with any image encoding method, which can be chosen for efficiency, resolution, and immunity to artifacts. The result is high-resolution, isotropic in any area of the brain, without signal dropouts or spatial distortion. This will be an important addition to the tools available to neuroscientists for studying brain activation. Specifically, this project aims to develop two different approaches for exploiting the SSFP response for fMRI. The first uses the frequency sensitivity of the SSFP transition band to detect absolute frequency shifts from blood oxygenation changes. The second exploits oxygen-dependent apparent T2 changes to the steady state magnetization. These techniques will then be evaluated and compared with conventional BOLD in well characterized studies of the visual system. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The overall goal of this work is to create an MRI imaging environment that eliminates the possibility of RF burns for recipients of cardiac pacemaker, deep brain stimulator, and other neuro-stimulator devices. Today, about 3 million Americans have implanted pacemakers that typically contraindicate any form of head, chest, or muskulo-skeletal MRI scan. Recent clinical safety studies for imaging device recipients at 1.5T have been performed without incident and no related fatalities for pacemakers have occurred since the 1980s. Guidelines for deep brain stimulator recipients typically require head transmit coils and only at 1.5T but at least two MR induced brain injuries have occurred at 1.0T. The general failure to identify adverse outcomes does not prove safety because these results cannot be extrapolated to other field strengths; guidelines are tied to scanner power which is reported inconsistently, and MRI systems lack robust methods of predicting and avoiding potential heating conditions based on physically existing preconditions. Improved engineering of the MR scanner itself can solve this problem. This will require an integration of electromagnetic safety sensors that can independently detect or search for dangerous resonances, MRI RF field mapping methods that can detect lead wire currents responsible for heating but at sensitivities well below physical heating thresholds, and distributed transmit array systems that deposit RF power only where needed. If the physical conditions for heating can be detected and imaged, regardless of field strength, patient orientation, or device, an RF excitation system can be designed to prevent heating. The aims of this research are to: 1) Develop an RF safety prescreen system to detect dangerous interactions before the MRI scan. Integrated external sensor systems will be developed for 1.5T, and extended to 3T. These systems will detect potential resonant device interactions that may produce RF heating and can be used before the patient even enters the MRI scan room. 2) Develop an MRI safety pre-scan to detect and quantify dangerous interactions with a low power MRI scan. MRI pulse sequences will detect and quantify induced RF currents on conductive structures, and use these measurements to grade risk, and predict potential heating for other sequences. 3) Develop safer MRI systems for the future using advanced RF transmission methods. Transmit array excitation systems and optimized pulse sequences will minimize electromagnetic coupling and RF heating near implanted devices. This will be tested in an in vivo animal model at 3T to show that RF currents on an implanted lead can be nulled while providing a sufficiently uniform RF field for imaging. .Ultimately, this work will lead to a clinically testable system. Achieving these goals will substantially increase access to MRI for a broad class of patients with cardiac or neuro-stimulator implants who are currently denied access out of fear of RF heating danger. PUBLIC HEALTH RELEVANCE: Technology to enhance RF safety in MRI scanners- is important to public health because it will enable the 3 million Americans with cardiac pacemakers or deep brain stimulator implants to safely undergo MRI exams without fear of unintended local RF burns. Underutilization of MRI scanners with these patients can be avoided, and the risk of adverse events or unsafe settings can be substantially eliminated.

DESCRIPTION (provided by applicant): The overall goal of this project is the development of an interactive, image-guided system for accurately placing ablation lesions in the left atrium for the treatment of arrythmias. Atrial fibrillation (AF) affects 10% of the population over age 70 and causes about 1/3 of strokes. Only 2/3 of percutaneous procedures for AF succeed even in carefully selected patients due to technical limitations in both visualizing tissue/device interaction and controlling catheter position. We believe that the combination in a single procedure of real-time visualization and guidance, interactive device control, and immediate lesion assessment will be critical in providing reliable, robust atrial ablation and will increase effectiveness far beyond the sum of the individual parts. Guidance and visualization will be provided by MRI, which permits real-time anatomic visualization, allows active tracking of devices, and provides many techniques for ablation monitoring and control. Intuitive, accurate access to the entire left atrium will be accomplished via an interactive, feedback controlled catheter manipulation system integrated with a real-time 3D visualization environment for navigation and device placement. This system will incorporate a haptic interface for robotic control integrating MR visual feedback catheter force feedback. Finally, direct MR visualization of acute lesions will provide immediate verification of ablative success. Imaging the lesion development will be accomplished via delayed enhancement, T2 weighted imaging, and a new MR RF current mapping technique that can potentially highlight tissue conductivity changes in the myocardium post-ablation. Specifically, our aims are to: 1) Develop improved MRI methods and devices for real-time 3D guidance during cardiac ablations. 2) Develop a general purpose intracardiac catheter system integrating sensory inputs and motor controls to provide precise control of the interventional catheter. 3) Develop and test real-time methods to assess tissue viability and electrical conductivity that can accurately predict and visualize the ablation pattern. The combination of visualization, guidance, and verification will allow quick, reliable atrial ablations, dramatically improving patient outcomes. The overarching objective of this proposal is to develop an integrated set of technologies to enable the imaging, mechanical, and control systems needed to replicate the surgeon's visualization, dexterity, and tools for performing percutaneous intracardiac surgery. This project will utilize a multi-disciplinary team (engineers, imaging scientists, and cardiologists) to address all the technical challenges in translating this system to clinical practice. Our initial focus will be intracardiac ablation of atrial fibrillation, given its prevalence, substantial clinical impact, and current suboptimal percutaneous success. This research - developing a minimally invasive system for atrial fibrillation procedures - is important to public health because it may allow many open-heart surgery procedures to be performed instead using less invasive catheters. This research also initially targets atrial fibrillation as it is very common (1 in 4 Americans develop it in their lifetime), leads to 1/3 of strokes, and there is a need for a successful method to cure it less invasively.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

This award permits Dr. Brian Wandell and his collaborators at Stanford University to purchase a 3T functional magnetic resonance imaging scanner. The shared instrument will be the centerpiece of a new facility, The Center for Neurobiological Imaging, designed to advance scientific research and training on topics spanning human decision-making, cognition, perception, child development, education and emotion. The instrument will be used to support research that advances understanding of the human brain and also offer the opportunity to integrate teaching about brain functions and systems into the curricula of students in a variety of fields. The instrument will increase the efficiency and quality of a broad array of scientific research efforts that aim to understand human brain function, and ultimately apply this new knowledge to the development of effective social, economic, educational and legal systems. The research approach involves a partnership between basic scientists and engineers. The advances in imaging over the last fifteen years are still in an early phase and within the next ten years, scientists believe, it should be possible to measure the distributions of particular molecules within the brain, trace brain development in detail and measure properties of the neuroglia. The close proximity in the laboratory between magnetic resonance physicists, statisticians, psychologists and other social scientists will make it possible to explore collaboratively new imaging modalities and transform technical advances into scientific insights. The instrument and related software and analysis tools will also be used to train graduate students and post-doctoral fellows in advanced methods for understanding the human brain.

Radiofrequency ablation (RFA) is emerging as an effective image-guided minimally invasive therapeutic alternative to surgical treatment of cancer tumors. RFA appears well suited to nonresectable tumors in liver. The ablation process is highly dependent on the electrical conductivity of these tissues yet there is no easy way to predict the current pathways or how focused the current will be on the tumor. For example, bone and fatty pockets can shield tumor from ablation currents. Consequently, repeatable ablation volumes are difficult to produce. Our goal is to enhance the planning, control and efficacy of tumor ablation by using an MRI system that can map RF ablation currents local to the electrodes during ablation and map thermal changes. RF current maps will show where power is being deposited, and MR thermometry will show where heat flowed during the ablation. Our approach exploits a new MRI technique that estimates RF current density in tissue. The ablation electrode can be injected with RF currents at the resonant frequency of the MRI scanner, and can also act as an MRI receiver. The MRI scanner can directly image the intense magnetic fields associated with the ablation current, and then derive the local electrode current flow to tissue. In our preliminary work, we have already visualized the current flow in an MR compatible ablation electrode. These tests demonstrated that fatty tissue effectively insulates and blocks the ablation current. Moreover, the current pathway itself lights up high conductivity tissue and creates a medically significant contrast. To fully exploit this capability, we will merge RF current mapping with MR thermometry and ablation devices to form a comprehensive interventional MRI system for RF ablation. Enhanced RF hardware, pulse sequences and reconstructions will be developed. Upon completion, we will perform ex-vivo tissue sample and in-vivo animal studies to demonstrate the clinical potential of this system.

DESCRIPTION (provided by applicant): Motivation: We aim to develop and implement new approaches to the design of high performance receive arrays for pediatric MRI. The ultimate goal is flexible, light, comfortable arrays that enable children to undergo MRI without anesthesia. This project builds on our success in Rapid, Robust Pediatric MRI EB R01009690, Vasanawala, PI. In it, the investigators of the current proposal developed and prototyped the first dedicated pediatric abdominal array coil, testing it on hundreds of children. This design is being commercialized by GE Healthcare, and is on the current product roadmap. This is a major advance for pediatric MRI. The enhanced sensitivity and parallel imaging capability of this array has been critical for developing highly accelerated imaging methods based on compressed sensing, parallel imaging, and adaptive motion correction that were the other aims of the previous R01. Over the last four years, these developments resulted in a 250% increase in pediatric body MRI utilization at our institution and a 50% decrease in CT. Approach: This was our first step towards making MRI much more accessible and effective for pediatric patients. We are already well along in the next steps, the subject of this proposal. The project proceeds in a sequence of developments that range from short term goals that will have immediate clinical and commercial impact, to intermediate and long term goals that will fundamentally change the way receive array coils are designed, constructed, and used. The motivation for this project is pediatric MRI, because these patients are the most sensitive to the environment, and would benefit most from less intrusive arrays with higher performance. However, once these technologies are established, we expect translation to all receive arrays. The project will proceed in three development aims followed by a clinical validation study. The first is to develop and fabricate a second generation pediatric array coil that is more flexible, so that it will confom to different size pediatric patients. We will pilot test the coil in the clinic to determine performance and patient acceptance. The second aim is to use printed electronics technology to fabricate array coils that are completely flexible, light and can be incorporated into children's garments or blankets. Various configurations of these flexible coils will be pilot tested in the clinic. The third aim is to develop small, low power, high performance electronics for flexible array coils, with the ultimate goal of completely wireless arrays. The results of this aim will be combined with developments of the second aim to achieve wireless completely flexible printed coils. Finally, the new coils will be tested in the clinic to determine their relative abilities toyield diagnostically successful exams on children of varying ages compared to current coil arrays. Significance: The result will be a revolutionary change in the way that receives arrays are designed, constructed and used. This will increase the capability of pediatric MRI, due to the better fit of the coils to anatomy. Coils will be less formidable and less intrusive, increasing children's' acceptance.

PROJECT SUMMARY The multidisciplinary T32 postdoctoral training program in Cardiovascular Imaging at Stanford (CVIS) is designed to train the next generation of cardiovascular imaging investigators by exposing them to three complementary areas ? clinical, engineering, and molecular imaging. With the rise in the impact of cardiovascular disease on U.S. and world health and the rapid advances in imaging technologies and cardiovascular biology, it is critical that the trainees be provided a broad, multidisciplinary and collaborative training program to foster their ability to translate cardiovascular imaging research into clinical applications. The program goals include rigorous training in the scientific method, critical analysis, logical reasoning and independent thinking in a highly collaborative setting. Trainees develop a focused area of cardiovascular imaging research expertise and exposure to a wide range of complementary research techniques. Mentors model collegial and productive collaboration, provide guidance in oral and written communication and instill respect for the responsible conduct of research. The program proposes to continue training 4 postdoctoral fellows in multidisciplinary cardiovascular imaging research. Fellows are appointed to the CVIS T32 annually, with a strong encouragement to seek their own funding for additional years as part of the skills imparted by the program. Eighteen trainees so far have benefited from this program, including 7 women and 2 underrepresented minorities. Three fellows are currently in training. Evaluations from the trainees suggest a high degree of satisfaction with the program. Many of the past trainees have gone on to become independent researchers in premier academic institutions and in industry. The Program is directed by Joseph Wu, MD, PhD (Contact PI), Professor of Radiology and Cardiovascular Medicine and Director of the Stanford Cardiovascular Institute (CVI); John Pauly, PhD, Professor of Electrical Engineering; and Koen Nieman, MD, PhD, Associate Professor of Radiology and Medicine (Cardiology) at Stanford University. Administrative and program management support is provided by a dedicated team of educators in the Stanford CVI. An Internal Advisory Board consisting of senior Stanford faculty from a broad range of disciplines and an External Advisory Board consisting of leading experts in cardiovascular imaging research in the U.S. play a vital role in monitoring the progress of this training program, providing ongoing support and advice as needed. The overarching goal of the program is to train the next generation of investigators with expertise in advanced cardiovascular imaging technology, dedicated to identifying innovative solutions, and capable of translating basic research into clinical success.

Project Abstract Motivation: We aim to develop and implement a new approach to transform pediatric MRI. The ultimate goal is ultra-fast and motion-robust imaging in a dedicated child-friendly environment to enable more children undergo MRI without anesthesia. For those who still require anesthesia, it will be briefer and lighter, and performed in a safer environment. This project leverages a small compact magnet, designed for adult brain MRI, with gradients that enable very fast imaging. With this magnet as an outstanding starting point, we will tailor our deep experience and multiple successes in developing new MRI approaches to high-density receiver coils, fast imaging sequences, and new image reconstruction methods to set a new standard for pediatric MRI. Approach: Although the compact scanner is designed for adult heads, with a 37 cm inner diameter, it can accommodate children under eight to ten years of age to image any body part. To transform this system for ideal pediatric scanning, three development aims will be pursued. The ?rst is to enable optimal signal reception. This will be accomplished through creating new receive chain electronics that are matched to the gradient capabilities, for ultra-high bandwidth imaging. This will be coupled to very thin and formed receive arrays that maximize the size of the patient that can be accommodated in the small bore of the scanner. The second aim is to develop methods of obtaining the highest performance out of the system by characterizing and correcting for its imperfections. This will be coupled to a bespoke approach to peripheral nerve stimulation, enabling maximal use of the gradients on each patient. These two developments will then be leveraged for high ef?ciency and motion robust noncartesian scanning. The ?nal aim is to develop a full environment and infrastructure that is well suited to pediatric imaging. Patient preparation and acclimation to MRI will be enhanced by virtual reality. Support equipment for anesthesia, new physiological sensors, and a novel child-friendly audiovisual system will be created. Signi?cance: The result of this project will be a revolutionary change in the way that MRI is used and per- formed for children. MRI will be more available, cheaper, safer, and have markedly improved image quality.