Russell S. Witte - US grants

DESCRIPTION (provided by applicant): Recurrent cardiac arrhythmia is a serious health concern affecting more than 4 million Americans and accounts for 20% of all deaths related to heart disease. In advanced cases when drug therapy is ineffective, arrhythmias are often treated with resynchronization or ablation therapy. Intracardiac ablation procedures to correct drug-resistant arrhythmias depend on accurate maps of the cardiac activation wave. Despite global success of interventional cardiac surgery for treatment of arrhythmias, electrophysiological (EP) mapping of the heart has significant limitations; for example, the complex and expensive procedure is prone to image registration errors, not effective for identifying transient arrhythmias, and has relatively poor spatial resolution (5-10 mm). To overcome several limitations and dramatically improve EP mapping procedures, we propose a novel modality for real-time imaging of current flow and biopotentials in the heart. As such, this project would develop Ultrasound Current Source Density Imaging (UCSDI) to greatly enhance and facilitate EP mapping of the heart. UCSDI is based on an acoustoelectric (AE) interaction between local pressure and resistivity to remotely detect current flow in tissue. As we have demonstrated in a variety of preparations, ultrasound passing through tissue generates a voltage modulation (the AE signal) close to the ultrasound frequency and proportional to the local current density. UCSDI would facilitate image guidance during ablation treatment of arrhythmias and other cardiac disorders through 1) direct 3D imaging of current flow and cardiac potentials in the heart; 2) enhanced spatial resolution determined primarily by the size of the ultrasound focus; and 3) automatic co-registration with pulse echo ultrasound (echocardiograms) for overlaying current flow maps with cardiac anatomy and motion. The following specific aims are central for testing this hypothesis. SA.1. Enhance UCSDI system hardware and software SA.2. Determine fundamental limits of sensitivity and resolution SA.3. Interface UCSDI system with commercial intracardiac catheter This project would dramatically improve our existing UCSDI system, identify limits of sensitivity and spatial resolution for EP mapping of the cardiac activation wave using UCSDI, and demonstrate feasibility using a clinical intracardiac catheter. A successful outcome would lead to a 5-year renewal focusing on in vivo studies and translation to the operating room. PUBLIC HEALTH RELEVANCE: This proposal will develop 3D ultrasound current source density imaging (UCSDI), a new modality based on an interaction between ultrasound and conductive tissue, to map electrical activity in the heart. An optimized imaging system would greatly facilitate and enhance electrophysiological mapping of the heart for treatment of arrhythmias.

? DESCRIPTION (provided by applicant): Our vision is to develop the first noninvasive, real-time and portable electrical brain mapping system based on disruptive acoustoelectric (AE) technology. Our goal is to overcome limitations with functional brain imaging and electroencephalography (EEG), which suffers from poor resolution and inaccuracies due to the blurring of electrical signals as they pass through the brain and skull. Acoustoelectric Brain Imaging (ABI) implements pulsed ultrasound (US) to transiently modulate local tissue resistivity. As the US interacts with neural currents, a voltage modulation (AE signal) is generated at the US frequency and detected by a distant electrode. This AE signal is proportional to the local current density and spatially confined to the US focus. By rapidly scanning a focused US beam in the brain and detecting the modulation signals, 4D ABI could achieve accurate, real-time, volumetric images of current densities through the adult human skull with a resolution near 1 mm3. Before transcranial ABI can be safely and effectively employed as a tool for functional human brain imaging, several major obstacles must be overcome. The greatest challenge is detecting the weak AE interaction signal through the skull, while maintaining safe US exposure to the head and brain. We, therefore, propose several strategies to dramatically enhance detection of the AE signal by a factor of 10 or more without compromising patient safety. Through a careful team-oriented planning process, we will design and develop the first ABI platform for evaluation and optimization in a realistic head phantom and, later, performance testing in living rat and pig brains. To address these and other challenges, we propose to 1) Develop the first-of-its-kind US delivery system capable of transcranial ABI; 2) Devise methods to dramatically improve detection of the AE signal through bone and define parameters for safe ultrasound delivery; 3) Apply ABI to map ? and ? oscillations in rat brain with validation usin standard electrophysiology; and 4) Apply and optimize ABI in pig brain (resting-state oscillations, evoked potentials, and induced seizures) compared with gold standard EEG. These aims interweave technology, innovation, modeling, and translation to overcome major obstacles in developing transcranial ABI for humans. They will be embedded in an interactive planning process that brings together wide-ranging ideas, challenging questions, and multidisciplinary expertise in medical imaging, ultrasound technology, neuroengineering, neurosurgery, neuroelectrophysiology, mathematics, psychology, and emergency medicine. The planning process will not only implement face-to-face meetings and site visits, but also social media (ABI.curiosityforall.org) and teleconferencing tools to maximize interaction, facilitate strategic planning, address safety issues, and overcome the Grand Brain Challenge posed by the skull. The project also establishes new collaborations with thought leaders at multiple institutions and industry to consider plans for point-of-care ABI in diverse settings. A safe, portable, and real-time platform designed for humans could transform our understanding of normal brain function and improve management (diagnose, stage, monitor, treat) of a wide variety of neurologic, psychiatric and behavioral disorders (e.g., epilepsy, depression, OCD).

DESCRIPTION (provided by applicant): Several million people in the U.S. suffer from overuse tendon injuries or tendinopathies, a common cause of pain and disability. One type, posterior tibial tendon dysfunction (PTTD), affects 3.3% of all women over the age of 40. While early signs manifest as tendonitis, the disease often progresses to severe flatfoot and can have a profound impact on ambulatory capacity. Because the severity and prognosis of PTTD are based on a subjective and imprecise physical exam, there is no way to predict which patients will do well with conservative bracing and therapy and which will ultimately require invasive surgery. This dilemma leads to prolonged unsuccessful conservative treatment in some patients and premature surgical intervention in others. Previous tendon studies strongly suggest that tendon disease and rehabilitation are closely associated with changes in the tendon's underlying composition and elasticity. Yet, there is no proven clinical tool to objectively and reliably measure tendon these properties in vivo. To address this limitation, we propose developing and testing ultrasound elasticity imaging (UEI) to quantify mechanical properties of the human PTT. Our objective is to gain an understanding of the relationship between tendon elasticity and the clinical severity of PTTD, the effect of tendon rehabilitation, and the prognosi for recovery. This project would 1) compare the mechanical properties of the PTT in patients with unilateral symptomatic flatfoot deformity with the contralateral control PTT, as well as that of healthy volunteers; 2) determine whether physical therapy induces mechanical changes in the PTT; and 3) determine whether UEI combined with discriminant functional analysis can predict the clinical outcome in subjects with advanced PTTD with the goal of determining group membership for new patients (conservative treatment or surgery). UEI has great potential as a portable, real-time, noninvasive modality to transform the current paradigm by providing a validated objective measure for evaluating tendinopathies, assisting with their prognosis, and prediction of clinical outcome from a particular therapy and its optimal timing. Success in this R21 project would justify a prospective clinical trial in a larger population to better define thresholds for predicting whether a particular patient should continue conservative treatment or opt for surgery. Such a prospective trial would ultimately determine the clinical usefulness of UEI in evidence based-management of PTTD (and possible other tendinopathies) and improving outcomes, including quality of life, in these patients.

ABSTRACT The University of Arizona (UA) High School Student NeuroResearch Program (HSNRP) introduces, trains, and nurtures a growing pipeline of diverse talented Arizona high school students, expanded by select progressing undergraduates, including a majority of underrepresented disadvantaged minorities in basic, translational, and clinical research on the normal and abnormal nervous system, neurological disorders, and stroke, and also encourages pursuit of advanced research experiences and fulfilling health/medical/science-related careers. We are leveraging the strong infrastructure, effective recruitment strategies, high level of student/faculty mentor participation, esprit-de-corps, and outstanding trainee productivity of our long-standing federally funded multidisciplinary/multispecialty disadvantaged high school student, undergraduate, and medical student summer research programs and year-round enrichment activities to energize the training model for this specialized NeuroResearch (NR) program. Fourteen-16 full-time 8-12 week summer high school and 4-6 undergraduate trainees annually for the next 5 years will be offered an expanding menu of closely mentored NR experiences; for retention in the pipeline, select HSNRP trainees will be subsequently reappointed for more advanced NR. Interacting together, these trainees will be integrated into an innovative, internationally recognized inquiry-based Summer Institute on Medical Ignorance (SIMI) which interweaves biomedical Knowns and Unknowns (what we know we don't know, don't know we don't know, and think we know but don't) with featured NR topics and mentor stories and sustains the momentum by periodic enrichment activities year-round. SIMI emphasizes translating translation and scientific questioning and includes a brief Introduction to Pathobiology and the language of medicine, topical seminars, laboratory/leadership/ multimedia skill workshops and practicums, clinical correlations, social networking, and career advising. A unique Virtual Clinical Research Center/Questionarium forms a mobile phone accessible-centerpiece platform for training and national/international networking. Within basic and clinical departments and specialized Centers of Excellence with enhanced Neuroscience emphasis and overseen by an energetic experienced multidiscplinary HSNRP Leadership Team and Advisory Committee, student research will encompass cross-cutting themes and in vivo, in vitro, in situ, in silico, and modeling approaches to neurobiology/disorders including Parkinson, Alzheimer, Niemann-Pick C diseases, ALS, epilepsy, HIV encephalopathy, head trauma, hydrocephalus, muscular dystrophy, pain/addiction pharmacology, molecular psychiatry, cognition, brain development, brain mapping, senescence, mental retardation, blood-brain barrier/neuroprotection, neuroimaging, neuro-genomics/proteomics, neuroengineering, deep brain stimulation, brain tumors, cerebrovascular disease, stroke, neurohealth disparities, and rehabilitation. Based on our ~29-year track record and established access to large diverse pools of disadvantaged Arizona students reflected in 615 SIMI-trained high school students followed to date with many in the basic/clinical NeuroResearch (undergraduate/graduate/ professional degree/biomedical-health career) pipeline, we expect HSNRP to continue to cultivate an expanding network of diverse and curious researchers, physicians and other health professionals; contribute to the NeuroResearch pipeline and enterprise; and improve neurohealth literacy through community engagement. Ongoing short-term and long-term evaluation includes surveys, database registry, curiosity scales, short- and long-term followup, and career portfolios to document efficacy and sustainability of the training model, promote diversity, and national/international networking.

ABSTRACT The overarching goal of this project is to optimize, validate and implement a revolutionary and safe modality for noninvasive functional imaging of neural currents deep in the human brain through the skull at unprecedented spatial and temporal resolution. Transcranial Acoustoelectric Brain Imaging (tABI) is a disruptive technology that exploits pulses of ultrasound (US) to transiently interact with physiologic current, producing a radiofrequency (RF) signature detected by one or more sensors (e.g., surface electrodes). By rapidly sweeping the US beam and simultaneously detecting these RF modulations, 4D high resolution current density maps are generated. This approach overcomes limitations with electroencephalography (EEG), which suffers from poor spatial resolution and inaccuracies due to blurring of electrical signals as they pass through the brain and skull, and, unlike fMRI and PET that measure slow ?intrinsic? signals, tABI directly maps fast time-varying current within a defined brain volume at the mm and ms scales. As a disruptive and scalable modality for noninvasive human brain imaging, tABI offers the following benefits: 1) High spatial resolution determined by the US focus (e.g., 0.3 ? 3 mm); 2) Real-time, volumetric imaging of local field potentials and evoked activity; 3) 4D imaging of neural currents from deep brain structures without assuming the conductivity distribution; and 4) Co-registration of neural currents (tABI) with brain structure, motion (pulse echo US) and cerebral blood flow (Doppler). Our multidisciplinary team of engineers, physicists, neuroscientists, psychologists, and imagers will overcome the primary challenge of detecting weak interaction signals through skull at safe US intensities. To demonstrate tABI as a safe and reliable modality for electrical brain imaging at the mm and ms scales in healthy volunteers, we propose to 1) Optimize, calibrate, and validate tABI using established human head and in vivo swine models; 2) Develop and validate the first tABI platform for functional brain imaging in human subjects; 2a) Assess extraoperative tABI for mapping patients with intractable epilepsy referred for surgery; and 2b) Assess tABI for mapping somatotopic organization in healthy volunteers. If successful, this project will deliver a safe, revolutionary and mobile technology for noninvasive human brain imaging with the goal of transforming our understanding of brain function and help diagnose, stage, monitor and treat a wide variety of neurologic (e.g., epilepsy, Parkinson?s), psychiatric (e.g., depression) and behavioral (e.g., OCD) disorders.