Peter T. Fox - US grants

Positron emission tomography (PET) provides non-invasive, quantitative, in vivo, measurements of regional cerebral blood flow (rCBF) and regional cerebral metabolic rate (rCMR) in man. Regional CBF and CMR vary directly with the regional rate of cerebral neuronal activity in the brain. Oxygen 15-H2O PET is a new PET methodology employing oxygen 15 in water (oxygen 15 half life = 123 sec) as a diffusible blood flow tracer to measure rCBF. Oxygen 15-H2O PET is uniquely suited to the study of focal cerebral function because of the brief (40 sec) scan duration, good resolution and the capacity for rapidly sequential scans (8 rCBF scans in 90 min) in a single individual. We propose to use oxygen 15-H2O PET to measure rCBF in normal volunteers during maneuvers designed to induce focal activations of discrete, cortical neuron populations. Initial studies will delineate response characteristics of somatic sensory neurons to electrocutaneous stimuli ranging in frequency from slow (2-10 Hz) to flutter (40-80 Hz) to vibration (100-500 Hz). Stimulus frequencies are chosen on the basis of the known response characteristics of cortical somatic sensory neurons in primates. When stimuli inducing consistent cortical rCBF responses are defined, they will be employed for more complex stimulus paradigms. Complex paradigms will be intended to induce focal cortical changes via cognitive tasks including pattern recognition, directed attention and language, all using somatic sensory stimuli as the vehicle. In this way the activation induced by the simple stimuli themselves will be well known, allowing discrimination of the regional changes due to the higher-order cognitive activity from rCBF change due to the stimulus alone. These experiments will provide a foundation for continued work on human cortical neurophysiology with the long-range intent of exploring progressively more complex human behaviors. Precise quantitation of the cortical CBF changes induced by simple, reproducible stimuli will also be the basis for studies of neurological pathophysiology, as these stimuli may then be used to generate cortical activation in individuals with neurological disease.

The overall objective of this research program is to enhance the precision and ease with which transcranial magnetic stimulation (TMS) can be used for the diagnosis and treatment of neurological and psychiatric disorders and for neuroscience research. This will be achieved through a coordinated program of technical developments, validations and theory-driven physiological experimentation which culminate in an aiming/holding robotic manipulandum for TMS (the TMS AHRM/TM; pronounced "arm"). The technical development program builds upon the capabilities of an FDA- approved neurosurgical robot (the NeuroMate), creating a new application for this device by extensive algorithmic developments and supportive mechanical developments. Algorithm developments target treatment planning and treatment delivery, including: algorithms for rapidly modeling the 3-D electric field created in the rain by a TMS coil at any external location; cortical surface modeling (extraction and visualization); scalar product (electric-field vector times cortical-surface vector) computation and visualization; and merging of functional images, structural images and treatment-planning models (surfaces & fields). Treatment-delivery tools include: frameless registration of head, brain image, and robot; fully automated robotic positions of the TMS coil; robotic sensing of TMS orientation (about a manually operated tool-rotation axis). Hardware extensions include: a passive digitizing arm, a TMS tool mount; a passive tool-rotation axis with an orientation sensor; and a general-purpose mobile cart. Technical validations measure the errors of each algorithm and procedure. Physiological validations test a new theory for modeling TMS local effects on the brain, called the Columnar Aiming Principles (CAPs). The technical development program will create an aiming/holding robotic manipulandum for TMS: the TMS AHRM/TM. The TMS AHRM/TM will greatly extend the capabilities of an FDA-approved medical robot, creating a prototype system for imaged-guided planning and robotic delivery for TMS. This prototype is intended for subsequent commercialization (e.g., through an SBIR award). In this proposal, a general aiming theory, the Columnar Aiming Principles (CAPs) for TMS will be validated. Collectively, these technical developments and physiological validations will create a system with wide potential for clinical and research applications.

The objective of this research proposal is to advance the use of quantitative metanalysis as a research method for human functional brain mapping. This will done by testing, refining and distributing strategies and software tools for metanalysis developed by the PI and colleagues at the University of Texas Health Science Center at San Antonio (UTHSCSA). Fox and colleagues have developed a new strategy for metanalytic modeling of the functional organization of the human brain-mapping literature, termed functional volumes models (FVM). FVM computes spatial probability profiles of the brain locations of mental operations. Fox and colleagues have also developed an electronic environment (BrainMap) for encoding, retrieval and visualization of the human brain mapping literature, as an aid to metanalysis. BrainMap includes a coding scheme (a hierarchical semantics) for the behaviors used and mental operations experimentally mapped, termed the Behavioral Coding Scheme (BCS). In the present proposal, the FVM metanalysis strategy (Aim 1) and the BCS (Aim 2) will be validated and refined in a collaboration between Fox and colleagues at UTHSCSA and the Washington University group of Raichle and Petersen. The FVM strategy will be validated by modeling 12, language-related brain areas using two, alternative strategies: original-data metanalysis and literature-based metanalysis (FVM). Original-data metanalysis will be made possible by accessing the extensive image-data archives of the participating groups. Modeling assumptions and results will be independently tested (Aim 1). The behavioral coding scheme will be validated by coding three, 30-paper samples from the brain-mapping literature and analyzing for comprehensivity, reproducibility, and accuracy (Aim 2). Validation of the BCS is a necessary precursor to investigator entry of data into BrainMap. General strategies and rules for metanalysis will be addressed at biannual workshops amongst grant personnel and invited consultants, including refinements of the FVM strategy, the BCS, and the BrainMap environment (Aim 3). BrainMap will be modified in an ongoing manner, to accommodate identified strategies, procedures, coding schemes and data produced by this project (Aim 3). Strategies and guidelines will also be presented to the community through publications and workshops at meetings of the brain mapping and informatics communities. As this approach to metanalysis is new and substantially different from prior forms of metanalysis, the field of informatics stands to benefit from the validation of a new analysis paradigm.

With National Science Foundation support, Dr. Xiong will develop imaging and modeling strategies to study mechanisms underlying adaptive changes of the human brain. The focus of this proposal is to explore the mechanisms underlying motor learning. Learning-induced neural plasticity and functional reorganization are well-established and well-documented, but not well-understood. Current neuroimaging studies investigate neural mechanisms underlying learning by exploring the changes in regional neural activity and inter-regional activity of task-performance. Little effort has been given to studying the more fundamental changes of neural connections and synaptic weighting. On the technical front, human functional imaging research sorely needs more rigorous approaches, as can be provided by mathematical modeling. A modeling framework - Structural Equation Modeling - is now accepted as appropriate for human imaging data. Structural equation modeling however, is currently performed with anatomical constraints based on neuroanatomical studies in non-human species. The performance of structural equation modeling might be greatly enhanced if anatomical constraints are individually optimized using the same subject's task-independent anatomical connectivity data. To date, this strategy has not been reported by any laboratory. The present proposal seeks to develop system-level modeling strategies for neuroimaging and to apply these novel strategies to mechanisms of action of motor learning. The overall goal of this proposal will be accomplished through the following four goals. First, developing and optimizing imaging strategies for detecting anatomical connectivity for each individual subject. Second, developing a structural equation modeling strategy by incorporating individual anatomical constraints to enhance those models' performance. Third, investigating changes in regional neural activity and inter-regional activity of task-performance induced by motor learning using the enhanced modeling strategy. Fourth, investigating synaptic plasticity by applying the enhanced modeling and demonstrating that synaptic plasticity is an underlying mechanism of action of motor learning. When completed, this research project will increase the understanding of mechanisms of adaptive learning and has the potential of defining a new strategy by which functional imaging can be applied to study mechanisms of action and disease pathophysiology.

DESCRIPTION (provided by applicant): The long-range goal of the research program initiated here is to develop 15O PET methods suitable for use in rats to investigate the temporal dynamics of experimentally induced stroke and the dynamics and mechanism of action of therapeutic interventions for stroke in quantitative and cost-efficient manner. In preliminary investigations to demonstrate feasibility, we have made significant progress in developing fully quantitative 15O PET methods for measuring blood flow (BF), metabolic rate of oxygen (MRO2) and oxygen extraction fraction (OEF) in the non-ischemic rat brain in vivo, without arterial sampling for arterial input function measurement; to our knowledge, we are the first laboratory in the world to do so. We now propose to complete the implementation and validation of these methods and to pioneer their application in the setting of experimentally induced stroke, including simple therapeutic interventions. The objective of this study, therefore, is to test the hypothesis that 0 PET measurements of BF, MRO? and OEF in rats can be utilized as an in vivo test module for the study of stroke and of therapeutic interventions in stroke. Our objective will be achieved via the following 3 specific aims. Aim 1: To develop methods for quantitative, PET measurements of BF, MRO2 and OEF in rat brain using bolus, intravenous administration of 15O tracers (H2 15O and O15O) and to validate these methods relative to intra-carotid injection of the same tracers in the setting of well-established physiological challenges. Aim 2: To apply methods for quantitative, PET measurements of BF, MRO2 and OEF in rat brain using bolus, intravenous administration of 15O tracers (H2 15O and O15O) in the setting of a stroke model. Aim 3: To apply methods for quantitative, PET measurements of BF, MRO2 and OEF in rat brain using bolus, intravenous administration of 15O tracers (H2 15O and O15O) in the setting of a therapeutic intervention applied in a model of acute stroke.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] This is a new proposal to establish a training program for medical students in neurological research. The overall goal of the program is to train medical students for independent careers in basic and translational research. Research in the field of human brain mapping (HBM), an experimental discipline that establishes structure-function correspondences in the brain through the combined application of experimental psychology, human neurological science, and non-invasive neuroimaging will be emphasized. In HBM, meta-analysis is a tool for modeling neural systems wherein statistically significant effects from multiple studies are combined to assess convergence and guide interpretation. The primary goal is to quantitatively determine locations of consistent activity within the literature for certain paradigm classes and/or behavioral domains. This research training program is focused on the meta-analysis method known as activation likelihood estimation (ALE), a new technique developed at Georgetown Univ. In ALE, input data are location coordinates placed on a 3D image matrix and blurred using a Gaussian spread function that approximates intersubject anatomical variability. Students will be guided towards performing their own meta analysis on a wide range of topics, including, but not limited to, working memory, emotion provocation, and word generation. The faculty members comprise an interactive cadre of MD and PhD scientists who possess extensive research and mentoring experience. We have specific plans for recruitment and for identifying candidates from underrepresented racial/ethnic groups that capitalizes on our regional and institutional demographics. The laboratory training in this program will be complemented by enrichment activities and didactic instruction concerning ethical issues in medical research and the responsible conduct of research. Program administration will be overseen with periodic evaluation and strategic planning input from an External Advisory Committee comprised of six scientists with expertise relevant to research training. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The overall objective of the present proposal is to develop, evaluate, distribute, and apply tools for quantitative meta-analysis of the human functional brain mapping (HFBM) literature. The BrainMap database may be used as an internet-based resource for retrieval, coding, and filtering papers that is required for an HFBM meta-analysis. BrainMap has been fully implemented in a multi-platform software environment (Java) and populated with >750 papers and >3,000 experiments (>20% of the literature meeting our inclusion criteria). It is now proposed: to extend the functionality of coordinate-based, voxel- wise meta-analysis (CVM) (Aim 1);to extend network analysis of CVM datasets (Aim 2);to create optimal high-resolution brain templates for spatial normalization that are representative of large groups of subjects (Aim 3);and to develop methods for returning functional labels and metrics of label likelihood for any given anatomical coordinate and serve these labels through a function-label extension of the Talairach Daemon (Aim 4). In addition, we propose a structured data-sharing plan that will provide a formal means for sharing software tools, meta-analyses, a functional ontology, and coordinate data of the published HFBM literature. Addressing these aims will greatly advance the current status of meta-analysis in functional neuroimaging. The evaluations associated with each development will provide guidance for further development of tools and logistics.

Acute; Adjuvant; Adjuvant Therapy; Apoplexy; CRISP; Cause of Death; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Chronic; Computer Retrieval of Information on Scientific Projects Database; Depression; Development; Diagnostic; Evoked Potentials, Motor; Functional Magnetic Resonance Imaging; Funding; Grant; Hand; Human; Human, General; Image; Institution; Invasive; Investigators; Learning; Light; MRI, Functional; Magnetic Resonance Imaging, Functional; Man (Taxonomy); Man, Modern; Measures; Mediating; Medical Imaging, Positron Emission Tomography; Mental Depression; Methods and Techniques; Methods, Other; Morbidity; Morbidity - disease rate; Motor; Motor Evoked Potentials; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neurologic; Neurological; Occupational Therapy; PET; PET Scan; PET imaging; PETSCAN; PETT; Patients; Performance; Personal Satisfaction; Photoradiation; Physiatric Procedure; Physical Medicine Procedure; Physical Therapeutics; Physical Therapy Procedure; Physical Therapy Techniques; Physical therapy; Physiotherapy; Physiotherapy (Techniques); Physiotherapy Procedure; Positron Emission Tomography Scan; Positron-Emission Tomography; Programs (PT); Programs [Publication Type]; Proton Magnetic Resonance Spectroscopic Imaging; Purpose; QOL; Quality of life; Rad.-PET; Range; Rate; Recruitment Activity; Research; Research Personnel; Research Resources; Researchers; Residual; Residual state; Resources; Site; Source; Stroke; Techniques; Therapeutic; United States National Institutes of Health; Vascular Accident, Brain; brain attack; cerebral vascular accident; developmental disease/disorder; developmental disorder; experiment; experimental research; experimental study; fMRI; imaging; improved; knowledge base; locomotor learning; motor learning; neuronal excitability; programs; recruit; research study; stroke; well-being

DESCRIPTION (provided by applicant): The purpose of this R21 is to develop a non-human primate (NHP) model of TMS brain stimulation. The long- range utility of a NHP model of TMS is to accelerate the pace of development of human treatments. At present, human treatment trials lack a strong theoretical or empirical basis for selecting optimal ranges for a myriad of treatment parameters, including stimulus location, stimulus intensity, stimulus rate and stimulus pulse pattern, session duration, session spacing and session number. While these treatment parameters could all be exhaustively explored in humans, this would be inordinately costly and time consuming. A NHP model, once developed, will allow a wide range of treatment parameters to be explored systematically in a rapid, cost- effective manner. We envision systematic exploration of treatment parameters as the theme of an RO1 to be submitted after the NHP model has been successfully implemented and validated through the proposed aims. As promising ranges of TMS treatment parameters are determined, this information will be translated from the NHP model for human treatment trials. The primary focus of this proposal is to characterize the magnitude and spatial distribution properties of TMS-driven cerebral responses in an anesthetized baboon model, thereby validating and calibrating this new model relative to our prior and ongoing human work. To achieve this, we will systematically vary the orientation and intensity of the TMS-induced E-field, while measuring the TMS-induced responses with PET and EMG as biomarkers. These two stimulation parameters (orientation and intensity) were chosen because our prior human electrophysiological and imaging studies have provided strong evidence that they jointly determine the spatial distribution and magnitude of the TMS-induced response. From these prior studies, the PI and colleagues have developed mathematical models which formalize the postulated relationships, making explicit predictions of response magnitude at each brain location for any given coil geometry, location, orientation, and current. Use of the same modeling constructs in NHP and humans will facilitate inter-species translation. This proposal has two Specific Aims. Aim 1 is to confirm the orientation response predictions of the C3 model (Fox et al., 2004) in the NHP. Aim 2 is to confirm the intensity response predictions of the PRP model (Capaday et al., 1997;Fox et al., 2006) in the NHP. PUBLIC HEALTH RELEVANCE: Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. To fully capitalize on the potential utility of TMS, a better understanding of the effects of basic TMS parameters on neurophysiology is needed. The long- range goal of the research program motivating this proposal is to develop a knowledge base capable of guiding the rational development of transcranial magnetic stimulation (TMS) as: 1) a potential treatment for neurological and psychiatric disorders;and, 2) a tool for mapping inter-regional connectivity and for quantifying changes in synaptic efficacy induced by learning and rehabilitation.

DESCRIPTION (provided by applicant): The overall goal of the proposed training program is to train physician scientists for careers in translational biomedical imaging research. This goal will be met through a unique 6-year, residency/PhD training program, which combines a radiology residency with a doctoral degree in imaging science (Rahal et al., 2007). This training program is hosted by the University of Texas Health Science Center at San Antonio (UTHSCSA), a large, research-oriented institution with outstanding imaging-research resources and a long history of federally funded, imaging research. UTHSCSA's radiology residency/PhD program consists of three clinical years (PGY- 1, -5, and -6), one didactic year (PGY-2) and two dissertation-research years (PGY-3, -4). Clinical training is via the Radiology Residency of the University of Texas Health Science Center at Scan Antonio (UTHSCSA). Coursework in imaging science is provided through the Radiological Sciences Program of the Graduate School of Biomedical Sciences, an American Association of Medical Physics approved program. Dissertation-research mentoring is provided by a combination of primary mentors and co-mentors. Primary mentors are experienced imaging-research faculty with a track record of promoting young careers. Co-mentors are established clinical or basic-science research faculty from a variety of departments, centers and institutes with a track record both of significant mentoring experience and of successful imaging-research collaborations with primary mentors. This 6-year residency/PhD pathway complies with the guidelines of the Holman Pathway of the American Board of Radiology (ABR). The Residency/PhD program is currently entering its eleventh year, admitting one residency/PhD trainee per year via the National Resident Matching Program. Applicants to this program are deeply committed to academic careers, choosing a demanding six-year training experience to optimally prepare themselves for today's highly competitive research arena.

Abstract ? Core D (NHP Imaging) The overall objective of Core D (Imaging Core) is to provide expertise and start-of-the-art technology for non- invasive imaging of experimental non-human primates (rhesus macaques) to achieve the goals of this HIVRAD Program. Core D is located in the Research Imaging Institute (RII) at the University of Texas Health Science Center - San Antonio (UTHSCSA), which is a short distance from the Texas Biomedical Research Institute (Texas Biomed)/Southwest National Primate Research Center (SNPRC). Core D will closely interact with the scientific Core C (Primate Core). Core D will also support the imaging studies outlined in Projects 1 and 3 of this Program Project. Imaging modalities to be utilized in these projects include positron emission tomography (PET) of copper-64 radiolabeled agents and magnetic resonance imaging (MRI). Specific Aims are: 1) Develop procedures for radiolabeling monoclonal antibodies, virus and vaccines for lymphatic localization and pharmacokinetic studies by PET imaging; 2) Develop imaging protocols for monitoring lymphatic drainage pathways and lymph node localization in rhesus macaques by PET and MRI; 3) Perform PET imaging studies of radiolabeled monoclonal antibodies administered by the intravenous or mucosal routes and radiolabeled virus by the mucosal route (Project 1); and 4) Perform PET imaging studies of vaccines in rhesus macaques administered subcutaneously or intranasally (Project 3). Vaccine components (amphiphilic or soluble peptide immunogen and amphiphilic or soluble CpG adjuvant) will be radiolabeled with copper-64 for lymph node targeting studies. There were approximately 44,000 new cases of HIV reported in the U.S. in 2011. Currently, no vaccine that prevents HIV acquisition is available. Also, most of these HIV cases were transmitted across a mucosal barrier. Imaging technology developed by this Core will be used by program scientists to understand the movement of virus and monoclonal antibodies across the mucosal barrier and assist in the characterization of new HIV vaccines. This project may lead to new radiolabeling techniques and new imaging protocol and image analysis methodology that can facilitate the development of effective HIV vaccines.

ABSTRACT Specific aims/significance. In our well-characterized baboon nonhuman primate (NHP) models of developmental programming and aging we use both categorical group and longitudinal, life course approaches to evaluate interactive programming-aging mechanisms. Developmental programming can be defined as responses to challenges in critical developmental time windows that alter life course phenotype. Premises/hypotheses. 1. Aging antecedents are present early in the hippocampal-hypothalamo-pituitary- adrenal (HHPA) axis (HHPAA), brain, and behavior; cardiovascular system (CVS); and metabolism. 2. Programming-aging interactions are major determinants of life course HHPA, brain, behavior, CVS, and metabolic health span. 3. Comparing normative, life course observational control data with data from three interventions that alter aging trajectory provides insights into key aging mechanisms and cellular pathways and information needed for translation to humans to anticipate age-related mechanisms that either increase or decrease health span. Findings enable development of markers and beneficial interventions in human aging. Projects - 1. HHPAA, Brain, and Behavior. 2: CVS Function. 3: Metabolism. Cores - A: Administrative; B: Animal; C: Genomics; D: MRI; E: Samples and Data Management. Synergy: All components study all 96 animals with in vivo MRI and tether studies and in vitro histological, cell culture, and molecular approaches. We study 96 baboons in 4 groups, equal males and females at 6?17 years (y) (human equivalent ~18?68y; 24? 68% of the life course). Groups: 1. 48 normal life course controls (NLC); 2. 16 IUGR offspring (F1) of moderately undernourished mothers; 3. 16 F1 of obese, over-nourished mothers; 4. In 16 at 12?17y we clamp plasma cortisol to normal 5y levels. Comparison of aging mechanisms in NLC and interventions provides information on life course whole animal and cellular mechanisms modified by programming-aging interactions. New preliminary data. We present new evidence of increased cortisol and accelerated brain, CVS, and metabolic aging in IUGR. Responsiveness to PAR-16-143 Complex Integrated Multi-Component Projects in Aging Research (U19). We address requested ?Large-scale longitudinal observational studies? integration of multiple outcomes with molecular, genetic, mechanistic data and interventions? animal models for aging- related conditions? multiple endpoints to elucidate mechanisms.? Investigators are from multiple institutions and have worked and published together in aging research and programming and in completing large NIH P01s, R24s, P51s. We share resources worldwide. Innovation. Life course NHP studies are rare. We assembled unique cohorts and built our own custom facility for these studies. We now 1. perform biopsies not euthanasia, enabling further applications on these cohorts; 2. combine U19 in vivo and in vitro data with histological and molecular data from our extensive fetal (130 fetuses) and postnatal archives (120 adults birth to 25y) to produce a new mechanistic programming and aging framework from womb to tomb.