John C. Gore - US grants

Contrast in NMR images arises primarily from the heterogeneous distribution of tissue relaxation properties, but the mechanisms by which NMR properties alter in disease states are poorly understood. In these studies, a systematic attempt will be made to comprehend and quantify the relaxation mechanisms in a single tissue, (rat liver) in both normal and diseased states. The methods used will be of general application and will be used to construct a model of the relaxation behaviour of other tissues. To accomplish this, NMR studies will be performed in vitro on preparations of isolated constituents of tissue to evaluate the significance of content alone and to quantify the relative efficacy of different macromolecules. Studies will also be performed on excised rat liver from normal animals as well as models of liver disease in which diverse alterations are expected. The NMR experiments will unravel which relaxation mechanisms are significant at the molecular level. Nuclear overhauser effects and deuterium quadrupolar relaxation rates in deuterated samples will be used to measure the contribution of non-dipolar mechanisms and to estimate the effective correlation time of tissue water. High resolution proton spectra of intact and deuterated tissues will reveal the behaviour of non-exchanging compartments. Saturation transfer and selective irradiation will be used to evaluate the contributions of chemical exchange and cross relaxation. Low temperature studies of the non-freezing tissue water will be used in combination with deuteration studies and NMR relaxation dispersion profiles over the range 10KHz - 100 MHz to quantify individual populations of protons, their mutual effects and correlation times. These measurements will be correlated with biochemical assays of tissue samples and repeated in rat models of normal, developing, regenerating, ischemic, malignant, cirrhotic and fatty livers. Animal imaging studies will also be performed on live rats at 85 MHz by recording chemical shift resolved images of liver. The normal liver and macromolecular studies will permit a thorough understanding of in vivo relaxation behaviour, and the animal model studies will provide experimental situations for evaluating the detailed nature of the changes in NMR parameters that accompany biochemical alterations in tissue.

The objective of the proposed studies is to better understand the fundamental mechanisms that determine the NMR relaxation properties of protons in tissues and the changes that occur in disease. The project will extend the methods developed in the previously funded period and pursue measurements to test specific hypotheses. Contrast in NMR images arises primarily from the heterogenous distribution of tissue relaxation properties but no adequate model exists to quantitatively account for the relaxation rates, especially 1/T2, even of normal tissues. There are, for example, major differences between the properties of macromolecules in solution and those of organized tissue. These differences include the magnitudes of cross-relaxation rates, chemical exchange and other T2 shortening phenomena such as diffusion effects and the importance of anisotropic motions of oriented water molecules. We will quantify the contributions of individual interactions and mechanisms that affect relaxation and identify those processes that contribute to T1 and T2 effects as well as those that affect T2 only. A variety of high resolution spectral techniques at 200-500 MHz, as well as T1 and T2 measurements from 2-500 MHz, will be used. We will measure (a) hydrodynamic effects, or the effects on water intramolecular dipolar interactions, using measurements of deuterium correlation times. (b) cross relaxation between water and macromolecular protons, using proton relaxation in deuterated samples and transient Overhauser effects (c) restricted diffusion in tissues, and its influence on the effective surface area seen by water, using pulse gradient spin echo sequences (d) chemical exchange rates between ionizable protons and water, using the method of Luz and Meiboom (e) diffusion amongst variations in magnetic susceptibility, using various spin echo sequences, theoretical modelling and the method of Karlicek and Lowe (f) the influence of water that is preferentially oriented and rotating anisotropically, using magic angle techniques and the method of Goldburg and Lee (g) paramagnetic interactions by studying the effects of chelates and heteronuclear NOEs. We will study a selected group of proteins, polymers and gels, in different conditions; in aggregates, in free solution or cross-linked and immobilized; in different degrees of denaturation, and in different solvents and buffers wherein the surface character and affinity will be affected. We will thereby assess the effects on water relaxation not only of individual macromolecules and constituents (and thus the significance of alterations in tissue composition alone) but also the role of supra-molecular macroscopic organization, such as molecular association, the formation of organelles, or immobilization in membranes. Measurements in tissues will be correlated with biochemical assays of tissues (protein, lipid, glycogen, water content) and other measures of the characteristics of the constituents. The overall project should provide many new insights into tissue relaxation phenomena to aid in the better understanding of the origin of contrast in NMR images.

This is an application for funds to upgrade and refurbish major components of an existing nuclear magnetic resonance animal imaging spectrometer. The deivce is a General Electric CSI-II system that is based on a 31 cm bore 2.0T magnet. It has been in constant intensive use at Yale University School of Medicine since November 1984, and was the third such system delivered by the manufacturer. Advances in the technology and methods of in vivo NMR imaging and spectroscopy have occurred since then that cannot accommodated on this system it uses a Nicolet computer that is no longer supported by the manufacturer, does not possess state of the art digital hardware or software, and its performance for imaging and localised spectroscopy is severely limited by the gradient system. However, it does have a magnet, RF spectrometer, and many other components that are all in excellent order, and has been well maintained by the existing user group. Since 1988 two major upgrades have been available for this system, and these are requested via application. The system is situated in the NMR Laboratory in the Department of Radiology which is component of the NMR Centre at Yale School of Medicine. The primary users will be from Diagnostic Radiology (to study proton relaxation mechanisms in tissues; for studies of diffusion in tissues; to evaluate effects of magnetic susceptibility variations in imaging, including susceptibility contrast materials; to devel fast echo planar and spin tagging techniques for studying myocardial wall motion; and to develop and evaluate F19 imaging as a tool for measuring tissue pO2); from Therapeutic Radiology (to develop NMR imaging as method of determining radiation dose distributions in irradiated gels); from Pediatrics and Neurology (to use p3l and H1 spectroscopy to evaluate the consequences of cerebral hypoxia in neonates); from Cardiology evaluate the effects of systemic acid-base disorders on myocardial energetics and pH regulation using NMR spectroscopy); from Molecular Biophysics and Biochemistry and Surgery (to study the regional metabolism and energy state of tissue skin grafts); and from Albert Einstein College of Medicine (to evaluate the changes in muscle in a rat model of sickle cell vaso-occlusion). The spectrometer would be devoted for 90% of its time to these projects. The NMR Research Group within Radiology comprises 4 Ph.D faculty physicists, 3 postdoctoral fellows, 2 electronic engineers, 2 research technologists and a part-time computer scientist, who would serve as the group to maintain and oversee the operation of the system. A committee of recognised experts in NMR and its application, drawn from within the Medical School and other parts of the University would act as an administrative advisory group. The overall aim of this application is to provide for the continuing demand for advanced NMR techniques in a wide variety of biomedical research for the next 5 to 10 years.

This proposal aims to evaluate the role of small scale susceptibility variations as a mechanism of contrast in NMR imaging. Susceptibility effects are important modifiers of the NMR signal from heterogeneous samples. Examples include the air spaces in lung, the trabeculae of bones, the flow dependent effects of blood in capillaries, and the mode of action of one class of NMR contrast agents, so-called susceptibility agents, which includes superparamagnetic iron oxide particles and lanthanide chelates. We will study the physical factors that are important in susceptibility related contrast, and aim to understand the mechanism of action and design factors for contrast materials. We will quantify the geometrical factors that influence such effects on NMR images to better understand susceptibility related transverse relaxation in complex media. Novel methods for measuring such effects on the magnetic environment of tissue water, including the use of pulse gradient spin echo (PGSE) measurements of apparent diffusion and multiple quantum line shape studies, will be used to characterize and compare different media and the effects of different agents. A specific aim is to better understand the factors that affect the ability of intravascular and interstitial susceptibility agents to relax tissue volumes not directly accessed by the agents, and to evaluate the dependence of relaxation rate on concentration and distribution in different compartments. We aim to test the hypotheses that the relaxation rate per unit concentration of agent varies with tissue type and is modified by blood flow. The design factors and mechanisms of action of susceptibility agents will be evaluated by theoretical computer modelling of the effects of susceptibility variations on the apparent transverse relaxation time and diffusion of solvent molecules undergoing Brownian motion and coherent flow. The influence of particle size, motion, spatial arrangement, magnetic moment, field strength and pulse sequence parameters, on the observed relaxation effects in gradient and spin echo techniques, will be investigated both by simulation and experimentally. The effects of compartmentation will be explored by simulation and by studies using agents entrapped in liposomes and capillary phantoms. The relaxation rate changes observed in different media will be evaluated by T2 and T1 relaxometry at various field strengths. We will quantify the contributions from dipolar effects, from bulk susceptibility line broadening, and from diffusion of water among the field gradients set up inside the medium. Using PGSE and multiple quantum line shape measurements we will directly measure properties of the local fields experienced by water molecules. These parameters will be correlated with the agents composition and distribution in tissue. In rats, the contributions to signal reduction that arise from susceptibility differences between the intra-and extra- vascular spaces will be evaluated in different organs and compared to the short range dipolar effects of agents such as Gd-DTPA. In this way we anticipate being able to evaluate whether susceptibility agents will be suited as markers for blood flow or other purposes, and to highlight design features that are important.

This proposal aims to continue studies to better understand the physical factors that affect the NMR relaxation properties of protons in tissues and which determine contrast in MR images. We aim to better understand what influences the fundamental processes involved in relaxation in tissues at the molecular level. We have provided evidence of the role of magnetization transfer (MT) in tissue-like model systems, and have shown how this depends on both chemical exchange and cross-relaxation, physico-chemical effects and macromolecular structure. This evidence has been derived by developing new and improved methods of measuring MT. We aim to extend these studies to other systems and tissues, and to more fully explore the molecular structural factors that influence MT and spin diffusion, and their roles in relaxation. This will include studies of the effects of surface groups, pH, and matrix rigidity. We will use novel quantitative methods of characterizing MT in media with different degrees of deuteration, along with new methods sensitive to T1rho, to derive measures of the sizes and motional characteristics of proton pools within samples. We will use these measurements to examine the number of compartments required to fully explain MT data. We will also directly address questions of the importance of MT versus spin locking and direct saturation effects. We will investigate the degree to which MT in tissues and model systems is limited by rates of water diffusion, by studying the effects of diffusion on displacement profiles of water using novel pulse gradient spin echo methods. Finally, we will try to detect and investigate the influence of water that is preferentially oriented and rotating anisotropically, using magic angle radiofrequency field techniques. We will explore the use of stimulated echo measurements of dipolar correlation effects and multiple quantum filter techniques that are sensitive to macroscopic order and relatively long time-scale residual dipolar couplings that are not motionally averaged and which may account for the shortening of T2 in tissues. We will study a selected group of tissues, biopolymers and gels, in different conditions and of varied composition. Overall this project should provide many new insights into tissue relaxation phenomena to aid in the better understanding of the origin of contrast in NMR images. This should in turn provide guidance on the interpretation of signals in conventional MR images and will motivate new approaches to tissue characterization.

This proposal is an application for funds to add special hardware and software to an existing whole body magnetic resonance imaging system that is dedicated to research studies only in order to permit ultra fast echo planar imaging (EPI) acquisitions in times substantially less than one second. This hardware comprises a replacement, high strength gradient coil and associated gradient amplifiers that can be very rapidly switched to produce multiple gradient echoes in a short time' There is also a dedicated computer and data acquisition system to permit multiple serial fast images to be acquired, stored, and displayed. The EPI capability will be important in several areas of application of MR imaging and is considered essential for progress in new directions in several funded projects. In particular, the ability of EPI to detect regional brain activation because of the accompanying alterations in blood oxygenation that in turn change the magnetic homogeneity of tissue, in response to specific appropriate stimuli, will likely produce important advances in our understanding of brain function and assist the diagnosis of different brain disorders. The application highlights funded research applications for functional brain imaging in the study of working memory and schizophrenia, for the depiction of specific areas involved in semantic processing in dyslexia, for localizing epileptic foci in refractory disease, for localization of motor and sensory areas, and for speech and, language areas. Functional brain imaging will form an essential component of major research programs in each of these areas. The stronger gradients will also permit artifact free diffusion weighted imaging to be performed in humans, which has important potential for the study of acute stroke and other conditions. The faster time resolution will also offer unique abilities for imaging the heart, and in our proposed studies these will be used for providing data for better quantifying regional myocardial wall motions in canines. These applications of the new facility will be supplemented by studies using the equipment designed to better understand the origins of contrast in diffusion weighted and susceptibility contrast imaging. All these projects will benefit considerably from the EPI upgrade and the combined effect of this work is likely to accelerate the introduction of fast imaging into clinical practice as well as basic research.

This proposal aims to develop an improved understanding of the mechanisms involved in functional MRI of the brain and to optimize imaging and data analysis strategies for the detection of neuronal activity. Functional MRI relies on the ability to detect the changes in NMR signal that are produced in discrete regions of cortex in response to specific activating stimuli, and are believed to reflect changes in local blood flow, volume and oxygenation. Functional MRI promises to be a major addition to the methods available for studying brain activation. Despite the widespread claims for the power and successes of the method, there remain several unanswered questions regarding its optimal mode of use, the tissue and technical factors that are important in determining the signal changes detected, and the significance and interpretation of these signal changes. The research proposed would systematically address such issues. The underlying mechanism may include both susceptibility contrast effects, based on the BOLD effect, as well as wash-in effects, and these will be separately quantified. The factors that affect each mechanism will be separately identified and measured. For the BOLD effect, extensive computer modeling and measurements in phantoms and animals brains will be used to establish the relative sensitivity to vascular structures of different sizes, spacings and orientations, as well as other tissue properties such as the rate of water diffusion. The separate sensitivities to s-called static field effects (T2*), diffusive losses and other mechanisms will also be established. The performance of different pulse sequences will be compared to devise optimal methods of scanning and detection at 1.5T. Echo planar imaging, conventional gradient echo and fast spin echo imaging as well as more novel schemes will be compared in phantoms, animal brains and examples of human activation. Human and animal activations will be produced in vivo using visual and motor stimuli as well as by alteration of global blood flow by acetazolamide and hypercarbia. A critical feature of current paradigms for detecting activation is the method of data analysis, which is interrelated with the nature of the task and imaging method used. We will compare different methods of analyzing functional data sets, including statistical parameter mapping, time-correlation analyses, and principal component analysis. The sensitivity of each to motion and other artifacts will be established by in in vivo comparisons and by computer simulations. From these studies, we anticipate being able to improve strategies for the use and interpretation of functional MRI in human studies of function and cognition.

The overall aims of this project are to provide a comprehensive and quantitative description of water diffusion in human brain which can be used to explain the variations in water diffusion that occur in normal and pathological conditions and that produce contrast in diffusion weighted MR images. There is now compelling evidence that water diffusion variations are of general interest and importance in a variety of normal and disease conditions. We aim specifically to understand the basis for the changes that occur in diffusion weighted imaging studies of stroke, seizure and neuronal activation. We aim to perform a series of exhaustive measurements of water diffusion properties in normal human brains. These studies will make use of the efficiency for collecting complete sets of data of advanced echo planar imaging techniques in humans to obtain measurements of the apparent diffusion coefficient (ADC) of tissue water, the degree to which diffusion is restricted, and assessments of the degree of diffusion anisotropy. These measurements will be used to infer the sizes of water compartments, the rates of exchange between them, and their intrinsic diffusion coefficients in brain tissues. Improved navigator echo methods will be implemented as well to permit high resolution diffusion images without echo planar acquisition. Measurements will also be made of the detailed nature of the transverse decay of tissue magnetization to permit the decomposition into component decay rates. Images of individual components of these so-called relaxation spectra will be produced and these should reveal correlative information on the spatial extent and exchange of different water environments. These measurements will be complemented with detailed studies of ADC in rat brain models of seizure and electroshock in which correlative electrophysiological measurements will be acquired. The threshold for observing diffusion changes following very brief stimulations will be established. We will also perform high resolution q space imaging of ex vivo preparations of excised rat optic nerve, subjected to different osmotic manipulations, to evaluate the effects of water volume shifts and other changes; and we will continue our extensive computer and theoretical modeling of water diffusion in restricted and compartmented systems to provide quantitative interpretations of these and other clinical observations. We will thereby obtain the information necessary to interpret water diffusion behavior in the brain, to guide the optimal use of MR imaging techniques in patient management and for developing models of tissue water diffusion to more fully explain the MRI changes seen in patients with stroke and other conditions.

This is an application for funds towards the purchase of a 3 Tesla (T) whole body NMR imaging system for use in research applications of functional magnetic resonance imaging (fMRI) of the human brain. It has become clear that the quality of information obtainable from higher field (>1.5T) MRI systems greatly exceeds that available from lower field devices. The recent development of higher field, actively shielded magnets at reasonable costs has greatly increased the practical importance and accessibility of high field NMR imaging. This proposal seeks partial support for installation of an advanced 3.0 T system at Yale University School of Medicine. to be manage by an expert group of NMR scientists and employed in a variety of experimental investigations. The increased signal to noise available at this higher field, and the improved gradient performance now available, will enable new experiments to be performed that currently are not possible with existing equipment. The increased signal to noise will permit anatomic imaging at sub-millimeter resolution, but will also greatly increase the sensitivity to detecting changes in susceptibility contrast, including transient early changes in MRI signal associated with neuronal activation. The higher field is considered essential for accentuating susceptibility contrast effects from alterations in blood oxygenation in the microvasculature that can be used to detect regional brain activation. The application highlights funded research applications for functional brain imaging in the study of working memory and attention, for the depiction of specific areas involved in language and reading, for localization of motor and sensory areas, for various aspects of visual processing, including processing of faces, for studies of impulse control, and the effects of various pharmacological agents. Studies will be performed in normal subjects as well as patients with various neurological or psychiatric conditions including schizophrenia, dyslexia, attention deficit disorder, Tourettes Syndrome, autism, epilepsy, and stroke. These applications will be supplemented by studies designed to better understand the origins of contrast in susceptibility contrast and high field imaging, as well as technical developments to improve the detection of neuronal activation and improvements in data analysis and interpretation. This resource will bring together diverse neuroscience specialists, physicists and data analysts to exploit imaging for obtaining new information on the functional architecture of the brain in normal behavior and disease. A high degree of synergy will occur between the various imaging studies, and the resource will be the primary system for advanced NMR applications serving an experienced community of users.

The overall purpose of the work proposed is to better understand the physical and physiological factors that affect the BOLD (blood oxygenation level dependent) signals detected in functional magnetic resonance imaging (fMRI). FMRI is a very important addition to the methods available for non-invasive mapping of the human brain, and is being widely used in clinical medicine as well as in basic studies of cognition. Although there is general agreement about how BOLD signals originate, there are still many features of the BOLD effect that are uncertain, and the influence of several factors is unknown, especially for so-called event-related fMRI. These deficits in understanding limit our ability to interpret fMRI data quantitatively. Furthermore, we do not understand well what limits the sensitivity of fMRI in practice, nor what gains may be possible as higher field strength magnets become more widely available. In the next phase of this grant we will quantify the effects of several technical and physical factors that modify the shape and amplitude of transient event-related fMRI responses. In both a rat model of somatosensory activation and human cortex, we will quantify the effects of field strength, pulse sequence, stimulation parameters, and intrinsic blood susceptibility, on the latency, magnitude and duration of event related responses, and verify these may add non-linearly when closely spaced. We will also quantify the effects of several physiological and pharmacological factors that commonly vary in humans subjects on the event-related responses, including the effects of altered basal flow, mild hypoglycemia, reduced hematocrit, levels of blood carbon monoxide, nicotine and caffeine, and estrogen, on the characteristics of the event-related BOLD signal. In order to clarify the validity of current models that are used to relate BOLD signals to underlying metabolic and physiological changes, we will measure the relationship between cerebral blood volume and flow in a rat model with graded hypercapnia and with neural stimulation, Finally, we will quantify and characterize the sources of noise that affect the fMRI signal. We will measure the contributions to signal variance that may arise from cardiac, respiratory, movements and vasomotor effects, and assess how these affect the fMRI signal/noise ratio, for different choices of technical factors including field strength, pulse sequence, echo time, and spatial resolution. These studies will further our efforts to understand and interpret data provided from fMRI better, and provide important insights into how to improve the quality of information obtainable by fMRI in diverse applications at different field strengths.

The studies proposed aim to develop improved polymer gels that may be used for accurate measurements of radiation dose distributions in three dimensions. Polymer gel dosimeters were first developed in our laboratory for use with MRI, which records the changes in NMR relaxation times of water protons produced by irradiation of mixtures of monomers in an aqueous gel. Such gels are tissue equivalent and provide unique and accurate measurements of integrated dose distributions in three dimensions with high spatial resolution. Nonetheless, there remain significant problems in the use of currently available polymer gels in practice that have limited their wider use. These include difficulties of preparation and storage of gels, which must be made and kept hypoxic until used and which therefore cannot be poured in plastic or arbitrary containers: their variable sensitivity, which largely arises from the influence of trace amounts of oxygen which inhibit their response: and the limited dose response, which is based on measuring changes in T2 values that are subject to errors. The studies proposed would lead to significantly improved gels that are more sensitive, more stable, and which can be made in a normal atmosphere and any container by a hospital physicist without special procedures. In preliminary studies we have produced gels in room air that are much more sensitive than current gels. These use a novel initiator system based on copper ion and ascorbic acid which combines with and requires molecular oxygen to start polymerization when the gel is irradiated. We will optimize the performance of these dosimeters by exploring the effects of different concentrations and components of this system. We have also shown that relaxation in irradiated gels occurs via magnetization transfer (MT) between free water and labile protons in contact with a semi-solid pool in the polymer. We will design and verify the performance of MT-sensitive sequences that avoid the pitfalls of T2 measurements for imaging gels to extract accurate dose information. We also postulate that the dose- response of polymer gels simply reflects a linear increase in the size of this semi-solid proton pool with increasing dose and we will perform novel NMR and other physical measurements to verify this model. Overall we aim to produce much improved gels for practical applications and obtain a better and more quantitative understanding of how they respond to radiation.

DESCRIPTION (provided by applicant): This is an application to establish a Bioengineering Research Partnership (BRP) to develop and integrate new technologies for the comprehensive mapping of human brain function. These will be used to study functionally connected networks within the brain and will provide the information for systems analyses of the neural bases of normal and abnormal behaviors. They will be applied to study development in children and infants, as well as the neurobiological basis of various psychiatric, developmental and neurological disorders. The BRP would develop non-invasive instrumentation, techniques and algorithms to acquire and combine the information obtainable from advanced high field magnetic resonance imaging (MRI) at 4 Tesla, near infra-red optical imaging, electrophysiology (including evoked responses), trans-magnetic stimulation (TMS), and computer data analysis and image processing. It would develop and validate novel means of performing functional imaging studies and of recording cognitive and physiological responses within the environment of a 4T imaging magnet, as well as methods to combine the information from the various complementary techniques involved. The partnership would bring together 6 core laboratories within Yale University, the host institution, and would also closely involve 8 collaborating corporate partners as well as investigators from 8 other universities (Vanderbilt, Columbia and New York Universities, UNC, UConn, Oregon Health Sciences Center, Medical College of South Carolina, and the Bronx VA Hospital). The BRP will include physicists, engineers, computer scientists, neuroscientists, psychologists, psychiatrists, pediatricians and radiologists. During Year 1 advanced functional imaging methods will be implemented at 4T, and the equipment needed for ERP and NW will be modified for use in the magnet. Similar developments of these modalities, of TMS and psychophysical techniques, will continue through years 2 and 3. The first three years of the BRP would focus on the development and validation of novel techniques for inducing and assessing brain activation in response to stimuli, while years 4 and 5 would focus more on developing methods for the integration of data obtainable by different means and for their analysis and interpretation in specific applications. The establishment of a BRP would be an ideal mechanism for bringing together different approaches to the study of brain function, and the integration of the various methods will provide a valuable new resource for neuroscience research whose capabilities will far exceed the sum of the separate components.

DESCRIPTION (provided by applicant): This application from Vanderbilt University seeks partial funding for the acquisition of a state-of-the-art, high field (9.4T) Magnetic Resonance Imaging/Spectroscopy system that will be used to extend and improve various research programs involving small animals. This system is essential for several current NIH-funded projects including studies of tumor biology, neural function and development, diabetes, alcoholism and transgenic mice. It is also essential for several projects that involve fundamental studies related to the further development and application of MRI methods in medicine. The proposed facility will provide a major new capability for in vivo imaging and spectroscopy and thereby will permit current NIH-funded investigators to undertake studies which are essential for their projects but which are currently unable to be performed without this instrument. Several previous studies have been obtained using an existing and antiquated 4.7T system that has numerous technical limitations and which is not able to provide the quality of information needed for these projects. The new, higher field instrument will acquire images and spectra that have inherently higher signal to noise ratios, greater spatial and spectral resolution, and images, which are more sensitive to some contrast mechanisms. The proposed system will have a much better shim and gradient system and associated hardware, and will be based around a modern console and spectrometer capable of a wider array of modern experiments. These new capabilities will include fast and 3D imaging that is important for a variety of experiments, improved diffusion weighted imaging, and broadband multi-nuclear (H-1, P-31 and C-13) in vivo MR spectroscopy for studies of metabolism. The system will be an integral part of a new Center dedicated to research imaging and will be supported by a large and experienced group of physicists, engineers and computer scientists, along with a well trained and qualified group of support staff, including electronic engineers and animal technologists. These technical experts will take responsibility for assisting users in experimental design, data acquisition and data analysis. The proposed instrument will be a multi-user facility, supervised by a director and a core staff, developed and managed via an operating committee, and with oversight by an advisory committee charged with the responsibility of assuring appropriate access to NIH funded investigators. The acquisition of the proposed instrument will significantly increase the number and quality of investigations using small animal MRI and MRS and in turn will help Vanderbilt University meet its commitment to enhancing bench-to-bedside research in the areas of basic cancer biology and cancer therapy, neuroscience, structural biology and genetics.

DESCRIPTION (provided by applicant): This application seeks support for a comprehensive postdoctoral training program in magnetic resonance imaging (MRI) and spectroscopy (MRS) at Vanderbilt University which will be provided by an experienced and expert group of faculty and research staff. MR methods are well established as amongst the most powerful and widespread of biomedical imaging techniques yet major advancements in technology and increases in their impact continue to occur. MR methods serve not only as the single most important modality in diagnostic imaging but also provide crucial insights into biological processes and structure to address fundamental questions in biomedical research. Advanced MR systems for research are available at a large number of medical centers, and further advances in their uses will occur inevitably as systems with stronger field magnets become more widespread. There is, however, a shortage and a critical need for appropriately trained scientists capable of exploiting the potential of MR techniques, who are aware of the uses and limitations of MR methods, and of how MRI/MRS may be implemented, advanced, and integrated with information available from other modalities. We propose a comprehensive training program designed for 8 outstanding postdoctoral scientists (4 in each of a two-year program) who will usually have had little previous significant experience in biomedical MRI and MRS. Postdoctoral trainees from physics, chemistry, biology, engineering or medicine will receive thorough and exemplary instruction in all of the cognate areas relevant to biomedical NMR in a coherent program that includes 18 Ph.D faculty experienced in biomedical MRI/S and their applications. This will be accomplished through an educational program, consisting of courses, seminars, and journal clubs; a practical program, consisting of faculty-led tutorials and practical training; and a research program, in which trainees will be integrated into an active research program. These programs illustrate most major aspects of the applications of MR methods in humans and animals and include functional and structural brain imaging, cancer biology, studies of basic relaxation phenomena and diffusion, blood flow and perfusion, metabolic imaging, image processing and analysis, and clinical MRS and MRI. Trainees will have access to outstanding facilities including human MR systems with field strengths of 1.5, 3, and 7T; animal MR systems of 4.7, 7, and 9.4T; and other imaging modalities (including optical imaging, microCT, and microPET). Trainees will be mentored in the ethics and methods of biomedical research, as well as in grant writing and other important career skills. The programs, personnel, and facilities at Vanderbilt provide unique opportunities for scientists to receive advanced training in biomedical NMR of the highest caliber, and will help to ensure that the remarkable insights into biology and disease that are possible with MRI and MRS will be realized.

The Small Animal Imaging Shared Resource is new within the VICC. It is dedicated to providing scientific and technical support for non-invasive imaging of small animals in vivo. The equipment and personnel necessary for this Shared Resource are provided by the Center for Small Animal Imaging, which was created at Vanderbilt University Medical Center as part of the newly-formed Vanderbilt Institute of Imaging Science. The use of in vivo imaging is a valuable and essential tool in diverse studies of tumor biology, especially in rat and mouse models, and a variety of anatomic, physiologic, pathologic and metabolic information can be obtained non-invasively from intact animals in series studies. Dr. John C. Gore is the Resource Director and facilitates investigators' research with the help of an expert staff dedicated to developing new and improved imaging methods and their applications; laboratory spaces for animal preparation and monitoring; computing Shared Resources for image analysis and processing; and an electronics workshop for development of instrumentation and other technical support. Dr. Gore has directed imaging research facilities for many years, and maintains an active research program developing and applying imaging methods in cancer and other areas. The faculty and staff of the Shared Resource are expert in different aspects of imaging science and stand ready to assist VICC investigators.

The role of the Center for Small Animal Imaging in the Vanderbilt University Institute of imaging Science in this P50 will be to develop and apply multi-modality imaging technologies for the comprehensive evaluation and characterization of the evolving minor microenvironment in the biological systems used to validate and provide input data for the mathematical models ef cancer. It will tbcus on combining the information from different modalities, including high field (9.4T) magnetic resonance imaging (MRI), bioluminescence, microCT, microPET, and ultrasound, to measure critical morphological, and biophysical features of in vitro and in vivo models of cancer to provide input for the mathematical models, and data with which to test model performance.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] This application seeks support for a comprehensive pre-doctoral training program in imaging science at Vanderbilt University which will be provided by an experienced and expert faculty and research staff. The field of in vivo medical imaging has developed from early uses of simple X-rays for diagnosis into a compendium of powerful techniques for patient care and the study of biological structure and function. Imaging in biomedical applications provides valuable information about tissue composition, morphology and function, as well as quantitative descriptions of many underlying biological processes. Continuing technical developments have expanded the applications of imaging to new areas of biology such as the study of gene expression in animals. There is a critical need for imaging specialists trained in different techniques and modalities, and able to relate imaging to applications in biology and medicine, and to make the connections between imaging and physiology, biological structure, metabolism, and cellular and molecular processes. The program proposed would provide graduate training in imaging science within the context of a leading research medical center, and dedicated Institute of Imaging Science, and strong science and engineering departments. We propose a comprehensive training program designed for 12 outstanding predoctoral scientists (6 in each of two years). We aim to recruit trainees into our existing biomedical engineering, physics, or molecular physiology and biophysics graduate programs. They will receive thorough and exemplary instruction in all of the cognate areas relevant to biomedical imaging in a coherent program that includes 23 Ph.D teaching faculty experienced in multimodality biomedical imaging and its applications. This will be accomplished through an educational program, consisting of courses, seminars, and journal clubs; a practical program, consisting of faculty-led tutorials and practical rotations; and a research program, in which trainees will be integrated into an active research program. The research opportunities include active projects in nearly all major imaging modalities and are especially strong in MRI, MRS, optical and nuclear imaging as well as image analysis. Trainees will have access to outstanding facilities including human MR systems with field strengths of 1.5, 3, and 7T; animal MR systems of 4.7, 7, and 9.4T; multi-system optical imaging including OCT, bioluminescence and multi-photon microscopy, microCT, microSPECT and microPET. Trainees will be mentored in the ethics and methods of biomedical research, as well as in grant writing and other important career skills. The programs, personnel, and facilities at Vanderbilt provide unique opportunities for predoctoral students to receive advanced training in biomedical imaging of the highest caliber. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Pancreatic islet transplantation holds great promise for the treatment of type 1 diabetes; recent advances in islet isolation and immunosuppression have led to improved results. However, the inability to noninvasively assess islet mass or number, to quantify islet blood flow, or to image islets within the pancreas or after transplantation limit experimental approaches to increase or sustain islet mass after transplantation and hamper studies of islet function or pathology during the development of type 1 and type 2 diabetes. Using approaches involving optical imaging, biomedical engineering, and transplantation of murine and human islets, our multidisciplinary team proposes to develop and apply new imaging technology to assess islet blood flow and to image islets within the pancreas and after transplantation. The proposed studies bring two distinguished investigators from the in vivo imaging area (Gore/Lepage) to work with two investigators already working in the area of type 1 diabetes and islet biology (Powers/Piston). By bringing together scientists from different disciplines, the proposed studies apply rapidly expanding imaging technology from other areas of biology to assess islet blood flow and to image islets within the pancreas and after transplantation. Experimental approaches will include transplantation of islets into the liver or beneath the renal or hepatic capsule of an immunodeficient mouse model that allows long-term survival of murine islet grafts and human islet xenografts (NOD-SCID mice), real-time imaging of blood flow, and magnetic resonance imaging. Islet mass, survival, and function will be correlated with measurements of islet blood flow and with islet imaging and characterization by magnetic resonance. These studies should discover new information applicable to islet transplantation in humans and the examination of events that cannot be examined directly in patients who have undergone islet transplantation. These studies will lead to the ability to assess islet mass within the pancreas and after transplantation and such technology will be useful to a variety of diabetes investigators interested in type 1diabetes and islet transplantation.

DESCRIPTION (provided by applicant): The overall aim of the studies proposed is to develop a comprehensive and quantitative understanding of the factors that affect the apparent diffusion rate of water and small metabolites in tissues, as measured using nuclear magnetic resonance. An improved model of water diffusion is needed in order to interpret the variations in apparent diffusion in normal tissues and pathological conditions which give rise to contrast in diffusion-weighted magnetic resonance imaging (DWI). DWI is useful for detecting ischemia and evaluating stroke, as well as for characterizing the state and response of tumors. We aim to clarify some specific controversies arising from previous studies of water diffusion, and to develop new insights into the structural features and physiological processes within tissues that affect apparent diffusion rates. In the next funding period we will further develop new methods to measure diffusion over much shorter times and finer spatial scales using so-called temporal diffusion spectroscopy, and will then apply these methods to derive new information on tissue structure and water compartments. We will also extend our studies to non-neural tissues and model systems. To achieve these aims we will implement oscillating gradient spin echo (OGSE) measurements of diffusion of water at 9.4T to probe tissue structure on a scale << 1 micron, and will record OGSE diffusion spectra over the range 0-100 kHz in tissues and tissue models. From these data we will extract the pore (cell) size, intrinsic water diffusion rates and surface to volume ratio of spaces within tissue. We will use the OGSE dispersion data and model fits to establish which of these parameters change as a result of various physiological perturbations. In addition, we will confirm the measurements and predictions from OGSE studies by performing elaborate computer simulations of water in realistic compartmental tissues and by other measurements and histology. We aim to perform measurements in a selection of carefully controlled samples (isolated rat optic nerve; perfused glial cell pellets; in synchronized HeLa cells at different phases of mitosis; in vitro in a perfused muscle preparation; and in mouse tissues in vivo and post-mortem) to extract new indices of tissue structure and the relationship of water diffusion behavior to basic tissue biophysical properties.

ABSTRACT NOT PROVIDED

[unreadable] DESCRIPTION (provided by applicant): The aims of the research proposed are to develop new magnetic resonance imaging methods that measure the apparent diffusion coefficient (ADC) of water in tissues as a function of temporal frequency, and to evaluate whether so-called diffusion spectra are useful for characterizing tumors and for monitoring their response to treatment. Variations of ADC of water occur within tissues in various pathological conditions including cancer, and give rise to the image contrast depicted in diffusion-weighted magnetic resonance imaging (DWI). Diffusion measurements have proven useful in small animal imaging for characterizing the state and response of tumors, and reveal information on tissue characteristics such as cellularity not obtainable by other means. Conventional measurements of ADC reveal the effects of restrictions to free diffusion on a specific spatial scale determined by the diffusion time interval, and typically this is several microns. Variations in ADC are thus dominated by variations in the density of restricting barriers of this spacing, and no information is available from ADC measurements about structural changes that occur at a smaller scale. We aim to develop a new approach to diffusion imaging by measuring so-called diffusion spectra using novel gradient waveforms. Measurements will thereby be obtained that are very sensitive to those structural features that affect restriction over very much shorter time scales. Images will thus be obtained in which the contrast is more sensitive to variations within cells. Oscillating gradient methods are uniquely capable of providing information on diffusion in the regime in which inferences can be drawn about the intracellular tissue structures that modify diffusion. We will further develop these methods to measure diffusion over much shorter times and finer spatial scales, and will then apply these methods to derive new information on tumors in vivo. To achieve these aims we will implement oscillating gradient spin echo (OGSE) measurements of diffusion of water at 9.4T to probe tissue structure on a scale " 1 micron. From these data we will produce images related to the pore (cell) size, intrinsic water diffusion rates and surface to volume ratio of spaces within tissues. We will establish whether OGSE methods can detect intracellular changes in cells following pharmacological treatments and during mitosis, and what changes are detectable in tumor bearing animals before and after treatment. The MR measurements will be correlated with histological image data and immunochemistry. In addition, we will predict the results of OGSE measurements by performing computer simulations of water in compartmental systems that replicate tissue structure. [unreadable] [unreadable]

This application seeks support for a new Small Animal Imaging Resource (SAIR) at Vanderbilt University, dedicated to providing scientific and technical resources and support for non-invasive imaging of small animal models of cancer in vivo. The equipment and personnel needed to support cancer imaging in small animals will be provided by a new center which provides access to a comprehensive array of imaging resources. The center currently allows state-of-the-art studies of small animals in vivo using high field MRI, X-ray CT, optical, ultrasound and nuclear imaging techniques including microPET and microSPECT. This new imaging center is currently housed in 4000 sq ft of space that has been completely renovated to house state-of-the-art instruments. The facility is supported by an expert faculty dedicated to developing new and improved imaging methods and their applications, contiguous laboratory spaces for animal preparation and monitoring, computing resources for image analysis and processing, and an electronics workshop for developing instrumentation and other technical support. The SAIR would further develop this infrastructure for cancer imaging, and would also advance and integrate new imaging technologies for the comprehensive evaluation and characterization of small animal models of cancer. Specific technological developments would be undertaken in MRI and microSPECT imaging. The SAIR would emphasize combining and integrating the information from different modalities to evaluate specific biological and molecular processes in mouse models. It would develop new imaging instruments and techniques, agents and algorithms to acquire and combine the information obtainable from high field (9.4T, 7T and 4.7T) MRI, novel optical imaging methods, microPET and microSPECT imaging, X-ray CT, ultrasound, imaging mass spectrometry (MALDI), and histology. It would support the development and application of new computer data analyses and image processing methods to combine and correlate these data sets, as well as the provision of a core resource for developing novel targeted contrast agents for each modality. These capabilities would be applied to several funded research projects, many of which are already using imaging extensively, including studies of specific molecular pathways and mechanisms in transgenic or xenograft mouse models of prostate, hepatocellular, pancreatic, breast, colorectal and skin cancers. The SAIR would be invaluable for supporting ongoing research in tumor biology and molecular imaging within a leading cancer center, and for training of cancer scientists in the applications of imaging methods.

[unreadable] DESCRIPTION (provided by applicant): This is an application for partial funding of a human-sized 7 Tesla magnetic resonance imaging (MRI) and spectroscopy (MRS) system at Vanderbilt University. This device will be used by over 25 established investigators in a variety of research applications and training programs. The high field system is required for research in 5 primary areas: [1] the development of advanced imaging and spectroscopic methods [2] studies of brain structure, organization and function in human subjects, for both basic neuroscience and with clinical applications in neurology and psychiatry [3] studies of brain structure, organization and function in large non-human primates [4] MRS studies of biochemistry and metabolism in vivo, with applications in muscle physiology, diabetes and other metabolic disorders [5] imaging and spectroscopic studies of cancer and the response of tumors to novel treatments. The scanner will be housed within a dedicated, new facility under construction for the Vanderbilt University Institute of Imaging Science (VUIIS), and would be a primary research resource for imaging scientists and trainees within the institute. MRI and MRS at high field provide many new challenges and may require new hardware design, imaging methods, and methods for image processing. An ambitious, state-of-the-art program of such developments will be undertaken. The 7T system will be used to explore advanced imaging methods that provide new information on the structure and biophysical properties of tissues. High angular resolution diffusion tensor imaging will also be developed, along with new functional MRI (fMRI) and multinuclear MRS methods for studies of brain and muscle, including the rate of turnover of neurotransmitters GABA and glutamate. Moreover, these MRI and MRS methods will be applied to non-human primates in combination with more invasive techniques that provide complementary information. MRS methods will also be used to provide insights into glucose transport and other metabolic pathways. The new instrument will be supported by an established group of MR imaging experts and support staff. The new 7T scanner would be a unique resource within the South East, serving research programs at Vanderbilt and at neighboring institutions including Meharry College, which serves large numbers of underrepresented minority students and faculty. A comprehensive plan has been developed for the financial and technical support of the scanner as well as for its management and use. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application seeks support for the renewal of a highly successful and productive Bioengineering Research Partnership (BRP) at Vanderbilt University which was first established in 2002. In the past 5 years this BRP has focused on the development and integration of multimodal measurements of human brain function. In the next phase, the BRP will be reconfigured to focus on the challenges of optimizing the quality of data obtainable using MRI and MRS at ultra-high field (7 Tesla) and of integrating multiple MR approaches to assessing human brain structure and function. This BRP will bring together 6 highly experienced laboratories and three corporations, as well as a substantial group of clinical advisors and users, to develop, integrate and evaluate improved methods for optimizing the information available from 7 Tesla brain studies. The BRP will be centered around a state-of-the-art 7 Tesla human MR system, and will develop novel technical solutions and scientific capabilities that in turn will provide dramatic new insights into brain structure and function. The Lead Investigators of the partnership from Vanderbilt will be John C. Gore (PI, who will also direct developments in Functional MRI Methods);Adam Anderson (Developments in High Resolution Diffusion Tensor Imaging);J. Christopher Gatenby (Developments in Imaging Physics and Engineering);Malcolm Avison (Developments in Magnetic Resonance Spectroscopy);Frank Tong (Visual Psychophysics, developing advanced methods of assessing the functional architecture of the cortex);Benoit Dawant (Image Analysis, developing algorithms for image processing and distortion corrections);and Limin Chen (Non- Human Primate Neuroscience, providing a core test-bed for many of the methods developed, and a unique facility for testing the absolute limits of performance of 7T studies). Dr. Craig Malloy of UTSW, Dallas will partner in the Development of Multinuclear MRS for assessing neurotransmitter synthesis and brain metabolism. The BRP will also involve the close cooperation of 3 corporations who will undertake to provide specific technical resources. The BRP will benefit from input from an expert group of Users and Advisors who will provide additional expertise to guide the research undertaken. The BRP would bring together and accelerate relevant ongoing research within these individual laboratories and provide the focus for integrating these different efforts in a highly synergistic manner. It will also provide unique training opportunities for imaging scientists, radiologists and neuroscientists."

ORGANIZATION AND ADMINISTRATION OF THE ICMIC [a] Structure and Advisory Groups The proposed ICMIC will be formed as a cohesive and interactive network of individual investigators and laboratories within Vanderbilt University, who will each undertake specific technical developments and research, but who will collaborate on the overall aims outlined in this proposal and use and support the Specialized Resources in an interactive manner. A critical mass of the personnel and laboratories involved (including the Small Animal Imaging and Chemistry Core laboratories and personnel, administrative personnel, director, 20 faculty and over 50 imaging trainees) are housed within contiguous spaces within our new VUIIS building, ensuring a very high degree of interaction. The new building will serve as the "home" for the ICMIC, and it will provide space for visitors and investigators from other departments so that they may physically reside at least part-time within the environment of the imaging facilities and core laboratories. The primary research projects and partnering laboratories from within Vanderbilt are identified in the figure below. The membership of ICMIC will not be restricted, and we expect it will grow over time, but at the time of writing this proposal we have identified key specific investigators who will take leading roles in establishing the resource and pushing its research agenda. These individuals are described below. In addition, although the progress and integration of the ICMIC will rely on frequent and informal contacts between the members, these interactions will be strengthened by an organizational structure designed to ensure the aims of the ICMIC are fulfilled. A schematic diagram the structure is given in Figure B1. The overall activities of the VICMIC will be overseen by the PI, Dr Gore, with administrative and other support from the Vanderbilt University Institute of Imaging Science (VUIIS, a trans-institutional coalition of imaging scientists and staff housed mainly within the Medical Center). Dr. Gore will take overall responsibility for the administration of the core resources and the integration of the other various activities of the ICMIC, but decisions on the scientific directions and allocation of resources will be shared with Dr. Dennis Hallahan (who will act as co-Director of the ICMIC) and other members of an Executive Steering Group. Dr. Dennis Hallahan is Professor and Chairman of the Department of Radiation Oncology, Ingram Professor of Cancer Research, and Program Leader for the Host-Tumor Interaction Program within VICC (see below).

This proposal aims to establish a new In Vivo Cellular and Molecular Imaging Center at Vanderbilt University which will be dedicated to providing the scientific and technical resources to develop, support and integrate highly innovative molecular imaging studies of cancer biology of direct relevance and translational potential to clinical cancer care. The proposed center will bring together an outstanding team of investigators from diverse disciplines, including leaders in imaging science, clinical oncology, the design and development of molecular probes, and cancer biology. The ICMIC will be housed in a leading medical center which is widely recognized for its highly collegial and interactive environment, and which emphasizes the importance of multidisciplinary approaches to medical research. The mission of the proposed ICMIC will be to develop and apply novel imaging biomarkers for the non-invasive, quantitative assessment of the molecular and cellular mechanisms of response to targeted treatment of tumors in vivo. The ICMIC will establish four Specialized Resources: a Small Animal Imaging Core;a Chemistry Core;a Radiochemistry Core;and a Biostatistics Core. These resources will support programs focused on the development and application of sensitive new imaging probes and methods for assessing how specific molecular signal transduction pathways, and the physiological sequelae to changes in these pathways, are modified by cancer and cancer therapy. The ICMIC will support 4 related major Projects. [1] Molecular Imaging to Evaluate EGFR and SRC-trageted therapies in Colorectal Cancer [2] Imaging Tumor Expression of Cyclooxygenase-2 [3] Noninvasive Assessment of Cancer Responsiveness to Therapy by use of Recombinant Peptide Ligands and [4] Proteolytic Beacons in the Non-invasive Assessment of Response to Cancer Therapy. All four projects will quantitatively and longitudinally assess the response mechanisms of novel, targeted anti-cancer treatments using novel, targeted imaging probes (via optical, PET, and SPECT) which will be complemented by measuring downstream physiological effects (via ultrasound, MRI, and CT). There will be synergy between the cores and the projects, which share common concepts of developing quantitative biomarkers of the effects of therapies that target specific cell signal transduction pathways. The ICMIC will also support new research directions via Discovery Grants for Pilot Projects, and undertake a program of Career Development to nurture scientists and physicians to become independent investigators in molecular imaging of cancer. The infrastructure and resources of the ICMIC will be provided by the Vanderbilt University Institute of Imaging Science, a key resource and program of the Vanderbilt-lngram Cancer Center, a leading comprehensive cancer center. The ICMIC will build upon existing programs, resources and institutional commitments to create an exemplary environment for research and training in molecular imaging.

Address; Analysis, Data; Animals; Area; Award; Biostatistics Core; Cancers; Charge; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Complement; Complement Proteins; Data Analyses; Development; Editorial Comment; Editorial Comment (PT); Educational workshop; Ensure; Funding; Goals; Grant; Guidelines; ICMIC; Instruction; Investigators; Malignant Neoplasms; Malignant Tumor; Method LOINC Axis 6; Methodology; Molecular Probes; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nature; Pilot Projects; Programs (PT); Programs [Publication Type]; Published Comment; R01 Mechanism; R01 Program; RPG; Range; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Research Resources; Researchers; Resources; Scientist; Source; Time; United States National Institutes of Health; Viewpoint; Viewpoint (PT); Workshop; in vivo Cellular and Molecular Imaging Centers; malignancy; molecular imaging; neoplasm/cancer; outreach program; pilot study; programs; research facility

CAREER DEVELOPMENT PROGRAM [a] Introduction The goal of our Career Development Program is to provide individuals with the training necessary for them to have successful and independent careers in translational research in molecular imaging in cancer. We envision supporting two categories of individuals: physician scientists who are in their first faculty appointment, and postdoctoral fellows with relevant Ph.D. degrees. The program will be administered by an ICMIC Career Development Program Committee appointed and overseen by the Executive Steering Group. Career Development is of vital importance for the future success of molecular imaging and to be able to exploit discoveries made in the laboratory for affecting clinical care. Funds administered by VICMIC will be used to promote multidisciplinary training and career development in molecular imaging in cancer in several ways. The funds provided by the ICMIC grant for these purposes will be supplemented by additional monies provided by our institution, as outlined in the accompanying letter from the Associate Vice-Chancellor for Research at VUMC, Dr. Jeff Balser. With the combined fund we will be able to support 2-3 VICMIC fellowships each year, which will be awarded competitively to appropriate individual applicants or nominees, normally for 2 years duration each. These will either be full-time postdoctoral fellowships for Ph.D.-educated trainees, or career development awards of significant salary support for junior faculty, including physician scientists with clinical training, as described below. However, it must be emphasized that VICMIC will be well placed to build on and benefit from the very large number of training and career development programs that exist at Vanderbilt, including some that are already dedicated to highly relevant areas of research in cancer and imaging. The activities of the ICMIC will complement these efforts. Molecular imaging is still an emerging area of research, and there is a continuing need to attract scientists from different disciplines to this field. For that to occur successfully, specialized training must be provided at many different levels, for faculty and staff as well as post-doctoral fellows and graduate students. Below we highlight some of the current programs at Vanderbilt that address those needs, and we also describe additional efforts that will be made by the ICMIC Career Development Program to invest our limited resources strategically for maximal effect. In recognition of the critical need for investigators in this area, VUMC has committed $100,000/yrto support additional trainees in molecular imaging in cancer through the ICMIC program. Therefore, in total, the Career Development Program will be able to fund 2 or 3 awardees per year. We have developed strong faculty interest in molecular imaging through our recent activities within VICC and VUIIS, and will continue to attract faculty involvement via increased outreach programs and the use of grants for pilot studies via the ICMIC Discovery Grant program. At the postdoctoral level, we have in recent years competed successfully for NCI and NIBIB post-doctoral training programs (T32 and R25 grants) in each of cancer biology, breast cancer, cancer imaging, magnetic resonance imaging and spectroscopy, and radiation biology (details are given below), so there are already significant numbers of positions for postdoctoral trainees who are permanent US residents working in this and closely related areas. The program directors and preceptors of these training grants are all closely associated with VICMIC, and we anticipate a continuing steady stream of postdoctoral fellows to undertake training within VICMIC from those programs. In addition, we already also have assorted NIH institutional T32 pre-doctoral training grants e.g. in biomedical imaging (from NIBIB, P.I. Dr. Gore), cancer biology, and other relevant disciplines. Several of our training grants support both pre and postdoctoral trainees. There is therefore a steady supply of graduate trainees from existing graduate Ph.D. and M.D. Ph.D. programs in biomedical engineering, biochemistry, physics, chemistry, electrical engineering, cancer biology, molecular physiology and biophysics, chemical and physical biology and the interdepartmental graduate program within the medical school (details of some of these are also given below). VUIIS faculty alone, for example, already supervise over 40 full time graduate students from these programs. These programs have strong educational components which are directly connected and overseen by the faculty within VICMIC and VUIIS. We therefore already have a substantial number of postdoctoral and pre-doctoral trainees in existing training programs engaged in molecular imaging in cancer and who would benefit from the VICMIC e.g. the 6 postdoctoral fellows supported by our R25 Cancer Imaging Training Program, and our 6 pre-doctoral trainees supported by our T32 in Biomedical Imaging. The majority of these trainees come either with strong backgrounds in physics, biomedical engineering or similar discipline, and they are then trained in biomedical applications, or they derive from biological sciences and learn technical aspects of imaging. There are already in place many lectures, lab rotations and enrichment programs to train experts in molecular imaging from these programs (some examples of relevant courses are described below). Our priorities for growth and investment of VICMIC funds will therefore occur mainly in two other areas of focus. First, we will provide fellowships consisting of salary support for junior faculty, trained in either basic or clinical sciences, to allow them to devote time and effort furthering their career development in molecular imaging. We will prioritize awards for qualified Physician Scientists in clinical departments with demonstrated potential to develop successful independent research careers at the interface of imaging and cancer care. We high- light below typical candidates for these awards selected from our current faculty and senior postdoctoral trainees. These individuals would identify research projects that match their interests and skills, but would have the time and resources to engage in further training in much the same way as K-awards awarded from NIH. Such fellowships would be invaluable for allowing promising investigators the time to develop independent research careers. These awards will be especially suited to postdoctoral fellows graduating from our training programs and for new clinical faculty interested in research careers. The criteria and selection process for these awards are described below. Second, despite our success in attracting and cultivating trainees with physical science backgrounds, within molecular imaging there is a chronic general shortage of appropriately trained postdoctoral chemists (organic, bio-, radio- or medicinal chemists, or individuals with skills bridging molecular biology and chemistry) With the interest and ability to contribute to molecular imaging. In many reports, this is the shortage that is identified as the major limitation on progress in the development of new imaging probes. We therefore will prioritize funds to support postdoctoral fellows with expertise and interest in chemistry, to train in cellular and molecular in vivo imaging and cancer biology. These opportunities will be directed specifically to graduating Ph.D. and M.D./Ph.D. students or new postdoctoral trainees interested in changing career directions to embrace the needs for targeted probe development in molecular imaging of cancer. Appropriate curricula of didactic and laboratory training will be developed to meet the specific needs of the different types of trainees, taken from the courses and rotations described below, to ensure they become experts in the important problems and opportunities for molecular imaging in cancer biology.

Project Summary/Abstract This application seeks support for a new, pre-doctoral educational and training program in Cellular and Molecular Imaging of Cancer at Vanderbilt University and Meharry Medical College. Biomedical imaging in vivo has developed from early uses of X-rays for diagnosis into a compendium of powerful techniques useful not only for patient care but also for the study of fundamental biological processes at the cellular and molecular levels. A variety of technical and molecular tools have evolved in recent years to propel cellular and molecular imaging into the forefront of cancer research. However, there is a critical need for scientists working at the interface of the physical and biological sciences to be trained in the ability to make the connections between imaging and basic biological processes in cancer. We propose to address this need with a comprehensive didactic educational and research training program designed for 10 outstanding pre-doctoral scientists (5 in each of two years). We will recruit trainees who have recently completed an undergraduate degree in a relevant science (particularly in Biomedical Engineering, Physics, Chemistry, Molecular Biophysics, Electrical Engineering or Biology) who will pursue research focused on molecular and/or cellular imaging of cancer. The didactic component of the proposed program will consist of courses, seminars, and a journal club. The courses will be organized into two tracks: one for those whose prior training emphasized relevant physical sciences and one for those with prior training in relevant biological sciences. The two tracks converge by the end of the second year so that all trainees, regardless of previous training, will be equipped with the necessary background to combine quantitative imaging and cancer biology at the highest levels. All trainees will be mentored in the ethics of biomedical research as well as in grant writing. Furthermore, both the didactic and research training components are designed to synthesize the physical and biological disciplines thereby creating a unique multi- and interdisciplinary training program for the study of cancer. For the research component, each trainee will have two mentors representing the disciplines of imaging science and cancer biology. Trainees will be integrated into ongoing NIH funded investigations within a leading biomedical imaging institute with strong connections and roots within a leading cancer center. By combining the resources and programs of the Vanderbilt University Institute of Imaging Science (VUIIS), the Vanderbilt-Ingram Cancer Center (VICC), and the Cancer Center at Meharry Medical College (CCM), we believe we have an outstanding infrastructure and personnel to create a leading, exemplary training program in cancer imaging. Narrative This application seeks support for a new, pre-doctoral educational and training program in Cellular and Molecular Imaging of Cancer at Vanderbilt University and Meharry Medical College. Biomedical imaging in vivo has developed from early uses of X-rays for diagnosis into a compendium of powerful techniques useful not only for patient care but also for the study of fundamental biological processes at the cellular and molecular levels. There is a critical need for scientists working at the interface of the physical and biological sciences to be trained in the ability to make the connections between imaging and basic biological processes in cancer.

DESCRIPTION (provided by applicant): This is an application for funding for an advanced 15 Tesla magnetic resonance imaging (MRI) and spectroscopy (MRS) system for studies of mice and other small animals, to be housed at Vanderbilt University. This device will be used by over 25 established investigators, many of whom are already expert in MR methods, in a variety of research applications and training programs. These research projects fall into 5 main categories: (1) Imaging science, the development of new and improved MR microscopic imaging methods at high field, and of a greater understanding of the nature of the new information provided, along with applications in mice: (2) Cancer, and the development and applications of MRI and MRS in the study of tumor biology in mouse models, including the development of imaging biomarkers to assess novel treatments for cancer: (3) Neuroscience, and the application of structural and functional MRI to studies of the architecture, metabolism and functional organization of the brain, especially the effects of specific genetic modifications and of novel pharmaceuticals: (4) Metabolic Disorders: the development and applications of advanced MRI and MRS methods to studies of metabolism and biochemistry in vivo, especially for mouse models of diabetes, obesity and other metabolic disorders. These projects would require approximately 80% use of the instrument. The remaining time available would be available for exploratory research and new directions. Each of these projects will benefit from the advantages of imaging at very high field, including gains in signal to noise ratio (SNR), improved spatial resolution, greater spectral resolution and sensitivity for MRS, and greater sensitivity for detecting changes caused by specific contrast mechanisms. The gains in SNR will overcome some of the practical limitations on advanced applications in mice that have been encountered at lower fields. The scanner will be housed and managed within the Vanderbilt University Institute of Imaging Science (VUIIS), and would be a primary research resource for imaging scientists and trainees within the institute. The new instrument will be supported by an established group of MR imaging experts and support staff. The new 15T scanner would be a unique resource within the South East, serving research programs at Vanderbilt and at neighboring institutions including Meharry College, which serves large numbers of under-represented minority students and faculty. A comprehensive plan has been developed for the financial and technical support of the scanner as well as for its management and use. PUBLIC HEALTH RELEVANCE: Magnetic resonance imaging and spectroscopy are widely used to obtain novel information on the structure, composition, metabolism and physiological function of tissues and organs. When applied to small animals (particularly genetically modified mice) these insights can be combined with other types of information (such as genetic, biochemical and behavioral data) to better understand complex biological questions. For studies in mice, smaller sized but stronger magnets can be used to achieve dramatic improvements in image quality at finer spatial resolution, thereby providing greater information. This proposal aims to procure a very high field (15 Tesla) magnet and associated hardware specially designed for mouse studies to be able to push the performance of MRI and MRS in numerous applications in cancer, neuroscience and metabolic disorders. The development and sale of such cutting-edge MR instruments will help create and maintain positions for skilled scientists and engineers with the manufacturers of the instrument and its parts, as well as expand opportunities for imaging specialists in academic and pharmaceutical research. The system has been designed to have minimal environmental impact and the major parts will be recycled at the end of its useful life.

American Association of Cancer Research; Antineoplastic Agents; Area; Association of American Cancer Institutes; base; Berlin; Biology; Cancer Biology; Cancer Center; Cancer Center Support Grant; cancer imaging; cancer research center director; cancer therapy; Chemicals; Clinical; Clinical Trials; Collaborations; Data; Detection; Development; Diagnosis; Doctor of Medicine; Doctor of Philosophy; drug discovery; Genetic screening method; Image; Individual; Institute of Medicine (U.S.); Institutes; Investigation; Jordan; Leadership; Malignant Neoplasms; Medicine; Mission; Oncologist; Patients; Phase; Policies; Positioning Attribute; pre-clinical; Prevention; programs; Proteomics; Research; Research Personnel; Resource Sharing; Role; Science; Technology; tumor; Wages

DESCRIPTION (provided by applicant): This R21 application aims to develop and evaluate a novel magnetic resonance imaging (MRI) technique that has considerable potential for detection and mapping of neural activity in the brain with temporal resolution much greater than BOLD (blood oxygen level dependent) imaging or similar approaches that rely on detecting hemodynamic changes. The proposed technique builds on provocative claims by established investigators that MRI methods that are sensitive to the diffusion properties of tissue water (diffusion-weighted MRI, DW-MRI) can detect water shifts and axonal swelling that accompany neural firing, phenomena that are not unexpected and have also been reported by optical imaging, and which occur immediately proximal in space and time to neural electrical activity. However, the origins and robustness of these changes remain controversial and unsubstantiated, and clearly are not easy to detect using conventional DW-MRI. We have pioneered a novel diffusion imaging method that can be selectively sensitized to neural structures of a specific dimension, and which should be much more sensitive to changes in the dimensions of neural cells and water compartments. We therefore propose to explore its use as a method of detecting and mapping brain activity. Conventional DW-MRI methods based on the Pulsed Gradient Spin Echo (PGSE) method reflect the integrated effects of a variety of structural features, including those of relatively large spatial scale, greater than a nerve cell diameter, including nerve cell membranes. We have developed an alternative technique, oscillating gradient spin-echo (OGSE), which is capable of detecting restrictions to diffusion over much smaller spatial scales, which results in a high sensitivity specifically to the effects of changes in cell dimensions. Here we propose to establish whether OGSE imaging can reliably detect immediate diffusion changes induced by neural activity. We will apply optimized OGSE, conventional BOLD and PGSE methods, to image rat brain in vivo before and after administration of a pharmacological agent (PCP) known to elicit robust, slowly varying changes in brain activation, with/or without pre-treatment with an agent that blocks the effect (BINA). These slow-varying activations will allow derivation of quantitative estimates of microstructural changes within the tissue. We will also record BOLD, OGSE and PGSE images at high temporal resolution during forepaw stimulation administered in an event-related design, during normal breathing or while breathing carbogen. By comparing the time courses of these various image series we will be able to verify whether diffusion changes related to activation are detectable, whether they occur faster than vascular changes, and whether the OGSE data at high frequency reveal changes in tissue microstructure (neuronal swelling) that occurs faster and more proximal to the underlying electrical events than other methods. The potential outcome of these studies would be a method for mapping neural activation with high temporal and spatial resolution that could be used in diverse human and animal studies of the functional organization of the brain. PUBLIC HEALTH RELEVANCE: There are widespread applications, in both neuroscience research and clinical neurological and psychiatric practice, for imaging methods that can detect and map brain activity to delineate and understand the functional organization of the brain. Functional MRI is currently the single most powerful method available for obtaining information on brain activation with high spatial resolution, but unfortunately it relies on blood flow changes that have very slow temporal characteristics, so that very little information is obtainable about the timing of neural events at the speed of the underlying electrical activity. The MRI method proposed for development may in principle overcome this shortcoming and allows recordings of brain activity with both high spatial and temporal resolution. The work would also substantiate or refute claims by others about the ability of MRI to assess neural activity with high temporal resolution.

DESCRIPTION (provided by applicant): The overall goals of this proposal are to quantitatively characterize the effects on neural activation and cerebral networks of novel compounds that target metabotropic glutamate receptor subype 2 (mGlu2) using functional neuroimaging techniques, and to correlate these findings with behavioral responses. These agents are of high interest as potential treatments for schizophrenia and other mood disorders. Preclinical and phase II clinical data with LY404039 support the hypothesis that metabotropic glutamate receptor subtype 2/3 (mGlu2/3) agonists are a viable, non-dopaminergic strategy for the treatment of schizophrenia. The clinical findings suggest that mGlu2/3 activation is effective in improving both positive and negative symptoms and a study in ketamine-induced working memory deficits in human subjects suggests that cognition can be improved, too. We have recently reported the development of a novel strategy to selectively activate individual mGlu subtypes, particularly mGlu2, using highly selective positive allosteric modulators (PAMs). These compounds do not activate mGlu2 directly, but dramatically potentiate the response of the receptor to Glu. The development of biphenyl indadone-A (BINA), a systemically active mGlu2 PAM that crosses the blood brain barrier, opens an unprecedented opportunity to investigate whether the antipsychotic-like effects of mGlu2/3 agonists can be recapitulated by targeting mGlu2 with a PAM. Our preliminary studies suggest that BINA has robust efficacy in several animal models used to predict antipsychotic efficacy. In the proposed studies, we will utilize BINA and the mGlu2/3 agonist LY404039 in a series of neuroimaging studies to test the hypothesis that selective potentiation of mGlu2 will have activity in animal models that predict antipsychotic efficacy. We hypothesize that these agents will modulate glutamatergic transmission in corticostriatal and corticothalamic circuits and that direct mGlu2/3 activation wil differentially modulate mesolimbic dopamine transmission compared to mGlu2 potentiation. Using resting state functional MRI as an output in NMDA receptor hypofunction models, we predict mGlu2-mediated normalization of neural network fluctuations. We will correlate the imaging findings with treatment effects on cognition tasks. Normalization of resting state brain fluctuations may be an important biomarker of the therapeutic efficacy of antipsychotic agents.

DESCRIPTION (provided by applicant): The overall aim of this proposal is to determine whether inter-regional correlations in resting state fluctuations of magnetic resonance (MRI) signals from the brain reliably measure functional connectivity between regions. The identification of patterns of highly correlated low frequency MRI signals in the resting state potentially provides a powerful approach to delineate and describe neural circuits. Moreover, observations of altered resting state connectivity in several disorders suggest these correlations reflect an important level of brain organization. However, although resting state correlations are already being widely used to assess brain functional architecture, their precise interpretation remains unclear, and whether they are direct indicators of functional connectivity is completely unsubstantiated. To investigate connectivity we will use very high- resolution MRI at high field (9.4T) to delineate cortical networks in anesthetized non-human primates. The sub- regions of SI cortex in monkeys are an excellent experimental model because the functional and anatomical structures of this region have previously been well investigated with invasive electrophysiological and histological methods. At 9.4T, fMRI acquisitions using vibrotactile stimuli identify functionally distinct cortical areas (3a, 3b and 1) within SI cortex, and each displays distinct fine-scale intra- and inter-regional, as well as longer range cortico-thalamic connectivity. We will (a) use stimulus-driven activation maps to identify candidate areas, and then measure resting state spatial connectivity patterns at sub-millimeter resolution in monkey brain; (b) measure the intrinsic point spread function of resting state BOLD, CBF (cerebral blood flow) and CBV (cerebral blood volume) correlations; and (c) determine how inter-regional correlations vary with functional role, spatial resolution and between BOLD, CBF and CBV signals. We will use simple multivariate models to reduce the data to a format by which they can be directly compared to electrophysiological measurements. We will then validate the measurements of connectivity from resting state MRI signals by direct comparisons with quantitative electrophysiology and histology in the same animals. We will (a) determine quantitatively the degree of spatial overlap of electrophysiologically defined neuronal response maps and resting state fMRI correlation maps: (b) determine what features of the spontaneous electrical recordings (multiple-unit spiking and local field potentials) from identified regions shw patterns of correlation similar to BOLD: (c) determine whether areas which appear to be functionally connected by BOLD and electrophysiology also exhibit strong inter-areal anatomical connections by injecting anatomical tracers into candidate regions identified by electrical mapping and fMRI and performing histological assessments post mortem. We believe that the proposed studies have considerable importance for better understanding the neural basis of resting state functional connectivity measures, and will have direct implications and impact on the applications of fMRI in both basic and clinical neuroscience.

DESCRIPTION (provided by applicant): This proposal aims to develop and evaluate novel magnetic resonance imaging methods to non-invasively detect and characterize functional networks in the human cervical spinal cord. These methods may be used clinically to establish the extent of injuries to the spinal cord and to monitor the progression of functional recovery afterwards, and may also facilitate earlier detection of several central nervous system pathologies. We propose to develop and evaluate functional magnetic resonance imaging (fMRI) to detect and quantify low-frequency fluctuations in baseline BOLD (blood oxygenation level dependent) signals as indicators of resting state functional connectivity in the human spinal cord. To date, over 2900 studies have used similar fMRI approaches to study functional connectivity in the brain, and have provided compelling evidence that low- frequency BOLD signal fluctuations are inherent in normal, healthy brains and represent an important level of organization of cortical function. However, to date no corresponding studies have conclusively demonstrated similar low-frequency correlations within spinal gray matter. The precise functioning of the spinal cord in both normal and pathological populations remains poorly understood even though studies of functional connectivity and plasticity in the spinal cord using methods other than MRI have been topics of intense research for the past two decades. The scarcity of fMRI studies mainly reflects the technical difficulties of performing fMRI in the spina cord, the failure to develop appropriate methods and coils, and the need for higher spatial resolution and greater sensitivity for imaging the spinal cord compared to the brain. We propose to address these technical challenges and limitations by using an ultra-high field (7 Tesla) MR scanner, novel fMRI image acquisition and data correction protocols, and a dedicated 16-channel radiofrequency coil array optimized for spinal imaging. The higher signal-to-noise ratio (SNR) and greater BOLD contrast from 7T fMRI has already shown significant advantages over lower field studies of the brain for detecting activation and measuring connectivity at high spatia resolution. The higher SNR permits the use of smaller voxels, and parallel coil arrays allow novel faster image acquisitions. Thus, ultra-high field MRI is uniquely poised to provide insights into spinal anatomy and functional connectivity that are not possible in practice at lower fields. We hypothesize that the proposed technical advances will be used to detect and characterize functional connectivity in the cervical spinal cord and changes that occur with injury, recovery and repair, and that these measures will complement information from other functional measures including task-based fMRI studies.

DESCRIPTION (provided by applicant): This is an application for an institutional pre-doctoral Ph.D. training program in biomedical imaging science submitted by faculty of the Vanderbilt University Institute of Imaging Science. The 31 preceptor faculty comprises an experienced and expert group of research scientists engaged in the development and applications of a comprehensive array of in vivo biomedical imaging methods. Imaging provides a compendium of powerful techniques not only for patient care but also the study of biological structure and function. Imaging can provide uniquely valuable information about tissue composition, morphology and function, as well as quantitative descriptions of many fundamental biological processes. Continuing technical developments have expanded the applications of imaging to new areas of biology such as the study of brain function and gene expression. There is a critical need for imaging scientists trained in different techniques and modalities, knowledgeable about the ideas that are common to all imaging, and able to relate imaging to applications in biology and medicine. Our program provides a comprehensive graduate training in imaging science within the context of a leading research medical center, a unique, dedicated Institute of Imaging Science, and strong science and engineering departments. We propose a comprehensive training program for 8 outstanding pre-doctoral scientists who would each be supported for 2 years. Students in biomedical imaging will be enrolled in one of several existing graduate programs but will mainly be admitted via our programs in Chemical and Physical Biology or Biomedical Engineering. We will emphasize recruiting graduates with backgrounds in the physical and quantitative sciences. Trainees will receive thorough and exemplary instruction in all of the cognate areas relevant to biomedical imaging and its applications. They will be co-mentored by imaging science faculty as well as collaborating clinicians and biological scientists. Although enrolled in different programs, all trainees in imaging will share a common set of courses, rotations and other experiences, which will overseen and administered by the Institute. The training program incorporates didactic courses, a program of rotations and research experiences, and a dissertation research project. The research opportunities include active, funded projects in nearly all major imaging modalities and areas of imaging science. Trainees have access to outstanding facilities including three research-dedicated human MR systems (2 at 3T and one 7T); animal MR systems at 4.7T, 7T, 9.4T and 15T; high resolution ultrasound imaging; X-ray and optical imaging; micros, microSPECT and micro PET; and extensive chemistry, radiochemistry and other laboratories. Trainees are mentored in the ethics and methods of biomedical research, as well as in grant writing and other important career skills. The programs, personnel, and facilities at Vanderbilt provide unique opportunities for pre-doctoral students to receive exemplary training in biomedical imaging science.

DESCRIPTION (provided by applicant): This proposal is being submitted as a companion grant to our application 2R01 CA109106 which was reviewed by the BMIT-B Study Section in June 2011 and awarded a priority score of 12 (2nd percentile) with no recommended budget cuts. Our overall aims are to continue the development, evaluation and validation of a novel magnetic resonance imaging (MRI) technique that is a sensitive indicator of tumor status, before and after treatment, and which provides unique information non-invasively on tissue microstructure. Grant CA109106 was subsequently awarded with a 62% budget reduction compared to what the Study Section recommended. The work being performed with that grant has therefore been amended and substantially reduced in scope, and it no longer will support most of the animal studies or comparisons of treatment effects that were proposed and approved. This proposal aims to secure supplementary support for those studies that were approved but not funded, and which we (and the Study Section) consider essential as part of our evaluation of this new methodology. Previous studies have convincingly shown that diffusion weighted MRI (DW-MRI) can report on changes in tumors during growth and following treatment. However, detectable changes occur only after a critical time has elapsed, when cell density has altered sufficiently, and conventional DW-MRI is not sensitive to earlier or more subtle changes within cells. We have developed an alternative technique, oscillating gradient spin-echo (OGSE) DW-MRI, which is uniquely sensitive to microstructural features much smaller than a cell which restrict the free diffusion of tissue water. OGSE measurements may be sensitized selectively to features of different sizes, they appear to be able to detect changes within cells before there are changes in cell density, and they provide a new type of spectral data which can be analyzed to obtain quantitative structural information. We have shown that OGSE imaging reveals greater heterogeneity within tumors, and at higher contrast, that it is sensitive to intra-cellular features such as nuclear size, and that it seems more sensitive to earlier changes in tumors following treatment. We propose to apply optimized OGSE methods to measure changes that occur with the growth of tumors, and in response to three different classes of targeted treatments, in mouse models in vivo. We will establish how early OGSE methods can detect the response of tumors to treatments, how well these changes predict later outcomes, and which OGSE parameters correlate with changes in cellularity, apoptosis and proliferation. The OGSE data will be correlated with co-registered quantitative histological and immunohistochemical sections of the same tumor to verify the interpretation of the measurements. We will also further assist the interpretation of OGSE data by performing elaborate computer simulations of water in compartmental systems of appropriate complexity. Our overall aim is to validate OGSE methods as an experimental tool for pre-clinical studies of tumors.

DESCRIPTION (provided by applicant): This application requests funds to purchase an integrated Positron Emission and X-ray Computed Tomography (PET-CT) Imaging system for use in numerous funded research studies involving human subjects or large animals at Vanderbilt University. PET imaging is the primary molecular imaging method available for non-invasive, translational human studies. Because of its high sensitivity and the availability of a wide range of biologically relevant radiotracers, PET can be used (amongst others) to detect and diagnose cancer, to assess specific cellular and molecular characteristics of tumors, to quantify brain neurochemistry and metabolism, to study the distributions and effects of novel pharmaceuticals, and to report on multiple cellular and molecular imaging biomarkers in a variety of important clinical applications. In the brain PET is uniquely capable of assessing neurotransmitter levels, occupancies and transport in neuropsychiatric applications, and is a crucial tool in the evaluation of novel drugs and interventions. In cancer, PET is a primary modality for use as a biomarker of tumor phenotype, treatment response and for characterizing the effects of novel targeted treatments at a molecular level. The uses and applications of PET rely on the availability of suitable radionuclides that are labeled with positron-emitting atoms such as 19F and 11C. Vanderbilt has a well- established PET Center and cyclotron, along with extensive radiochemistry laboratories and personnel, but the only PET scanner reliably available for research studies is a microPET that cannot accommodate people or large animals. The requested instrument would meet the extensive demand for research PET studies of humans and large animals in a leading medical center. Moreover, as all modern PET scanners also incorporate CT for co-registration, the proposed instrument would also provide access for research CT studies as well. Although we possess dedicated CT scanners for small animals, we have no research CT capability for human subjects and imaging of large animals is not allowed by law on our clinical systems. The PET-CT scanner would provide new types of information that will complement and enhance the ongoing research of numerous NIH-funded projects, SPORES and Centers, and would be a unique resource for multiple investigators. The Radiochemistry Center at Vanderbilt is experienced in producing an array of compounds that will be used to study tumor metabolism, hypoxia and proliferation, the expression levels of specific cell receptors and proteins, and various neuroreceptors, transporters and modulators. Several of the CT applications are focused on the development of image-guided interventions. The system will be housed and managed in a dedicated Institute of Imaging Science that is experienced in providing and operating major core shared research resources for investigators, and will be supported by an expert staff and user group. A comprehensive plan for Administration and Financial Management of the resource has been developed.

? DESCRIPTION (provided by applicant): This is an application for funding to upgrade an existing 7- Tesla magnetic resonance imaging (MRI) and spectroscopy (MRS) system that has been in use for a decade at Vanderbilt University for studies of mice and rats. The upgrade (a replacement console, including main computer, spectrometer and RF modules, but not including the magnet and gradient subsystem) is required (a) because after 10 years the system is no longer state-of-the-art and its performance limits ongoing research projects but also (b) the manufacturer (Agilent) will no longer (since October 2013) remain in the business of small animal MRI, provide upgrades, maintain hardware or support the system in a satisfactory way. The upgrade will ensure the continuing productivity of this important resource, and at the same time provide enhanced capabilities. This device will be used by over 16 established investigators, all of whom are already experienced users of the 7T scanner, in a variety of research applications and training programs. These research projects fall into 4 main categories: (1) Imaging physics, the development of new and improved MR imaging methods at high field, and of a greater understanding of the nature of the new information provided, along with applications in small animals: (2) Cancer, and the development and applications of MRI and MRS for the study of tumor biology in small animal models, including the development of imaging biomarkers to assess novel treatments for cancer: (3) Neuroscience, and the application of structural and functional MRI to studies of the architecture and functional organization of the brain, especially the effects of specific genetic modifications and of novel pharmaceuticals: (4) Metabolic Disorders, and the development and applications of advanced MRI and MRS methods to studies of physiology and biochemistry in vivo. The projects of the 9 Major Users would require approximately 68% use of the instrument, the Minor Users would require about 20% of the time, and the remaining time available would be available for exploratory research and new directions. Each of the projects will benefit from the advantages of imaging at 7T, including high signal to noise ratio (SNR), high spatial resolution, excellent spectral resolution for MRS, and high sensitivity for detecting changes caused by specific contrast mechanisms and agents. The scanner will be housed and managed within the Vanderbilt University Institute of Imaging Science (VUIIS), and will remain a primary research resource for a large group of imaging scientists and trainees. The instrument will be supported by an established group of MR imaging experts and support staff. A comprehensive plan has been developed for the financial and technical support of the scanner as well as for its management and use, and the system is assured of strong institutional support and oversight.

? DESCRIPTION (provided by applicant): This is an application for funding to replace and upgrade a 3 Tesla magnetic resonance imaging (MRI) and spectroscopy (MRS) system for human subjects that has been in use for research full-time for over a decade at Vanderbilt University. The current scanner is heavily used by over 60 active investigators with NIH funding who rely on high quality MRI and MRS data for diverse research applications. We aim to install a 3Tesla 70-cm bore Ingenia scanner manufactured by Philips Healthcare to replace the existing scanner, which is an aging system no longer fully supported by the manufacturer. MRI is well established as the single most powerful non-invasive imaging modality for studies of soft-tissues. MRI and MRS can be used to provide uniquely valuable information about tissue composition, morphology and function, as well as quantitative descriptions of many underlying biological processes. Our current system unfortunately precludes the exploration of several new avenues of MR research and some new applications are beyond the capabilities of our current machine. The new system will provide three major specific advantages. [1] it will be able to implement new methods such as multi-band acquisitions that cannot be implemented on the current platform, and investigators can be assured of continuing support for several years; [2] it has a larger bore, so we can image larger patients that currently are excluded from studies, and achieve higher RF and main field uniformity. The larger bore is essential to meet the challenges of our local population and to permit more and better studies of the abdomen, spine and breast; [3] the new all-digital architecture with direct conversion of MR signals within the RF coils produces images with higher (40%) signal to noise ratio. In this application we feature 29 selected investigators all of whom are experienced users of the current 3T scanner, in a variety of research applications. Their research projects fall into 4 main categories: (1) Imaging physics, the development of new and improved MR imaging methods: (2) Cancer, and applications of MRI and MRS for diagnosis and clinical management, including the development of imaging biomarkers to assess treatments: (3) Neuroscience, and the application of structural and functional MRI to studies of the architecture and functional organization of the brain, in normal as well as neuropsychiatric conditions: (4) Metabolic Disorders, and the development and applications of advanced MR methods to studies of physiology and biochemistry in vivo. The projects of the Users described herein would require approximately 80% of the useable time available on the scanner, and the remainder would be used for exploratory research and new directions. The scanner will be housed and managed within the Vanderbilt University Institute of Imaging Science, and will remain a primary research resource for a large group of imaging scientists. The instrument will be supported by an established group of MR imaging experts and support staff. A comprehensive plan has been developed for the financial and technical support of the system as well as for its management, and the system is assured of strong institutional support and oversight.

? DESCRIPTION (provided by applicant): The goals of this proposal are to further investigate and evaluate recent new discoveries about the nature of temporal variations in magnetic resonance imaging (MRI) signals from the human brain, acquired in a resting state, which potentially provide a completely new basis for quantifying the functional architecture of white matter. We have recently shown that local inter-voxel correlations between resting state signal fluctuations within white matter are spatially anisotropic. Measurements of these anisotropic correlations and subsequent analyses permit the derivation of a new mathematical descriptor, a functional connectivity tensor (FCT) that quantifies the functional synchronization between neighboring voxels and delineates longer range dynamic connections. Some of the features of FCTs superficially closely resemble the appearance of diffusion tensor imaging (DTI) data across large brain regions but without the use of any diffusion gradients and based on completely different biophysical phenomena. This discovery demonstrates that white matter tracts exhibit functional, temporal variations which in turn suggest a new approach for integrating functional and structural information. The construction and analysis of FCTs permits tractography of functional pathways that often appear to follow white matter tracts, potentially revealing directions of flow of neural information. Furthermore, the functional tensors appear to change in response to neural stimulation, even though task-activation of white matter has proven elusive. Resting state connectivity has been extensively used to delineate functional circuits within the cortex but to date has been completely overlooked in white matter, and current opinions are biased against being able to detect neural activity in white matter using MRI. The objectives of this research therefore are to construct functional connectivity tensors in normal brains at rest, compare these to underlying structural features, and elucidate the underlying biophysical mechanisms that account for their origins. Our specific aims are (i) to measure and characterize functional connectivity tensors in a resting state in normal subjects, assess their reproducibility, and determine how they depend on specific technical aspects of acquisition and post- processing; we will quantitatively assess whether FCT data conform to white matter tracts, which may be achieved by analyses of FCT and DTI atlases created from a population of normal subjects co-registered to the same space; (ii) to investigate the biophysical origins of resting state correlational anisotropy in humans, and how they vary with stimulation; and (iii) to validate the basis and interpretation of these correlations by high field studies of nn-human primates, in which we will determine whether the correlations originate from hemodynamic changes and how they relate to underlying neural electrical activity. Overall, these will be the first comprehensive evaluations of our novel observations of anisotropy of correlations in resting state MRI signals from white matter. The proposed use of FCTs for mapping of brain functional connectivity is compelling and offers to advance our understanding of the functional organization of complex neural networks in the brain.

? DESCRIPTION (provided by applicant): This proposal aims to detect and characterize inter-regional correlations in resting-state fluctuations of functional magnetic resonance (fMRI) signals within the spinal cord (SC), and to validate their neuronal and anatomical bases as measures of functional connectivity. Our discovery of synchronized variations of MRI signals between the various horns of spinal cord grey matter in humans and monkeys suggest these patterns depict neural circuits of functional significance. Moreover, their changes post-injury suggest they may provide practical imaging biomarkers of functional integrity. Our earlier studies in human subjects have stimulated this parallel program of research using non-human primates (NHPs). We will use very high-resolution imaging at high field (9.4T) to study networks in the grey matter of the spines of anesthetized monkeys, extending our previous studies of the functional organization of primary somatosensory cortex. Although there have been several 1000s of studies reported that have used resting state fMRI to detect and characterize functional connectivity in the brain, to date there have been only a handful of studies of task-induced activation, and no previous reliable findings of resting state fluctuations, in the grey matter of the SC. Our preliminary studies in humans and NHPs have adduced strong evidence that resting state variations are reliably measurable, reproducible, and produce patterns depicting distinct neural circuits within and across spinal segments. However, although resting state correlations in brain are already being widely exploited, their precise interpretation remain unclear, and their biophysical basis as indicators of functional connectivity is unsubstantiated. This is even more the case in the spine, where we have much less knowledge of the detailed vascular physiology or organization of specific functional neural circuits. We therefore propose [1] to characterize the spatial connectivity patterns of resting state fMRI signals at sub-millimetr resolution in the spinal cords of NHPs; [2] validate the connectivity measures from resting state fMRI signals by comparisons with quantitative electrophysiology and histology; and [3] validate the interpretation of connectivity measures from resting state MRI signals by comparisons before and after pharmacological manipulations and spinal cord injury. We will acquire resting state fMRI data, perform electrophysiological measurements, evaluate behavior and quantify connectivity from post-mortem histology in monkeys before and after unilateral transectional injuries to the spine, and after pharmacological modulation of afferent inputs. Overall, this research would establish new insights into the functional architecture of the SC and provide new opportunities to investigate SC function in normal and pathological conditions. It would provide a firm foundation for the application of resting state MRI to assess the functional integrity and recovery post-injury of the spine in patients suffering a variety of disorders of the SC.

Abstract / Summary This proposal aims to extend the work performed under a recent R21 exploratory grant to detect and validate measures of functional connectivity in the human cervical spinal cord (SC) using resting state functional MRI (rsfMRI). The delineation and characterization of neural circuits within the cord may provide a valuable imaging biomarker of functional integrity of the spine applicable to a wide range of disorders. The identification of patterns of highly correlated low frequency blood oxygenation level dependent (BOLD) signals in a resting state has provided a powerful approach to delineate and describe neural circuits in the brain. We recently reported the first reliable detection of similarly correlated low frequency signal fluctuations in SC in a resting state in normal subjects, and showed how functional connectivity may be quantified in the SC both within and between segments. Moreover, in parallel studies in non-human primates we have shown that these spine circuits are selectively and specifically altered by injury and revert back over time in a manner that correlates with functional recovery. We have also shown how multi- parametric MRI can be used to derive quantitative indices of tissue composition and structure which can be related to the functional changes. We hypothesize that the intrinsic neural circuits revealed by rsfMRI in the SC are an important representation of neural synchrony within spinal segments that in turn are an essential feature of normal functions; and that alterations in the patterns of functional connectivity may be used as non-invasive imaging biomarkers of the effects of injury and of therapeutic interventions. We aim (1) to further develop robust, reliable methods to detect and quantify functional connectivity in human SC by optimizing the acquisition and analysis of images at 3T; (2) to implement a novel, multi-parametric spine MRI protocol incorporating diffusion tensor imaging and quantitative magnetization transfer imaging which provide maps of quantitative indices of tissue microstructure and composition; (3) to validate the interpretation of functional connectivity measurements and accompanying changes in white matter composition and microstructure as objective biomarkers of spinal integrity and for guiding clinical management decisions. Imaging data will be correlated with a battery of physical assessments of function in subjects with a wide range of functional impairments to demonstrate their clinical relevance. We will also evaluate their capacity for monitoring and predicting outcome of treatments in patients with cervical spondylotic myelopathy (CSM) and with traumatic spine cord injuries (SCI). The significance of the work is that it will use novel MRI methods that have proven successful in studies of the brain to objectively evaluate functional circuits within the SC, and show that connectivity measures can assess and predict clinically-relevant functions and symptoms. The ability to assess functional integrity has widespread potential for characterizing injuries to the cord, their changes over time, and for assessing novel therapies.

Summary / Abstract This is an application for funding to replace and upgrade an IVIS 200 optical imaging system that has been in use for 12 years at Vanderbilt University for diverse fluorescent and bioluminescent studies of mice and small rats in vivo. The upgrade to an IVIS Spectrum system (a replacement which includes a sensitive optical imaging system, computer, and anesthesia modules) is required (a) because after 12 years the IVIS 200 system is no longer state-of-the-art and its performance limits ongoing research projects but also (b) the manufacturer (now owned by PerkinElmer) will no longer (since 2014) maintain crucial hardware components or support the system in a satisfactory way. The upgrade will ensure the continuing productivity of this important resource, and at the same time provide enhanced capabilities. This device has been used by over 80 established investigators over the past 5 years, and in this application we feature a selected 19 investigators all of whom are experienced users of the current IVIS 200 scanner, in a variety of research applications and training programs. These research projects fall into 4 main categories: (1) Molecular imaging probe development, the production of new and improved optical imaging probes, along with applications in small animals; (2) Cancer, and the development and applications of bioluminescence and fluorescence imaging for the study of tumor biology in small animal models, including the development of imaging biomarkers to assess novel treatments for cancer; (3) Neuroscience, and the application of optical imaging to studies of the brain, especially the effects of specific genetic modifications and of novel pharmaceuticals; (4) Metabolic Disorders, and the development and applications of optical imaging methods to studies of physiology and biochemistry in vivo. The projects of 12 Major Users would require approximately 65% use of the instrument, the listed 8 Minor Users would require about 25% of the time, and the remaining time available would be available for exploratory research and new directions. There are a much larger number of investigators who are also minor users. Each of the projects will benefit from the advantages of the IVIS Spectrum system, including the ability to acquire co-registered bioluminescence and fluorescence tomographic images on a single system; spectral unmixing algorithms to minimize autofluorescence and image multiple fluorescent probes simultaneously; and transillumination excitation geometry for detecting and quantifying deep tissue fluorescent sources. The IVIS Spectrum will be housed and managed within the Vanderbilt University Institute of Imaging Science (VUIIS), and will remain a primary research resource for a large group of imaging scientists and trainees. The instrument will be supported by an established group of optical imaging experts and support staff. A comprehensive plan has been developed for the financial and technical support of the system as well as for its management and use, and the system is assured of strong institutional support and oversight.

Summary This proposal aims to develop and validate MRI methods that exploit novel contrast mechanisms based on chemical exchange and diffusion which can detect changes in the tissue microenvironment, quantify intrinsic micro-structural features, and promise to improve the ability to discriminate pathological processes. These studies will provide imaging biomarkers that can quantitatively describe tissue microstructure and composition in diseases including tumors and stroke, and provide new information for both clinical and pre-clinical applications. At higher field strengths (3T and above) different relaxation mechanisms dominate the behaviors of MR signals compared to lower fields, providing new opportunities to characterize tissues. In particular, spin- lattice relaxation rates (R1?) in the rotating frame using spin-locking sequences become dominated by exchange effects rather than by dipole-dipole interactions, with additional contributions from diffusion through susceptibility gradients that mimic exchange. These processes are affected by very different factors than dipolar interactions, and they can be exploited to provide new types of image contrast. Moreover, R1? varies with the locking field amplitude, and that variation (the R1? dispersion or R1?D) provides a way to derive the parameters of the exchange or to produce new types of parametric images that are sensitive to the changes that occur with pathology. The proposal therefore has three main goals. [1] We have analyzed and measured the effects of diffusion through magnetically inhomogeneous media on R1?D and shown how dephasing effects in the presence of microscopic field gradients from variations in susceptibility produce changes in R1? over a range of low locking field amplitudes. Analysis of this dispersion gives the magnitudes and spatial scales of field gradients, and reveals the dimensions of magnetic inhomogeneities within tissues, such as the micro- vasculature. We will show how such spin lock methods can be used to characterize the dimensions of the micro-vasculature in the normal brain and tumors, and validate the results using quantitative microscopic imaging and other methods. [2] We will also further develop, interpret and apply R1?D imaging at higher locking fields in order to measure proton exchange rates and create new types of parametric image that emphasize the contributions of protons exchanging at specific rates. Moreover, we aim to show these exchange-sensitive images detect early changes in stroke, are affected by pH, and can detect the administration of exogenous ?exchange contrast? agents. We will thus show R1?D imaging provides a novel approach to exploiting exchange-based effects with some advantages compared to techniques such as CEST. [3] Finally, we will demonstrate these methods can be translated to clinical applications and will optimize their implementation, demonstrate their ability to produce novel parametric images based on diffusive and chemical exchange, and assess their reproducibility at 3T. Overall these studies will provide a firm foundation and validation for the use of a new class of exchange-sensitive MR images for clinical and pre-clinical applications.

Abstract The proposed research aims to measure blood oxygenation level dependent (BOLD) signals in white matter (WM) using functional magnetic resonance imaging (fMRI), validate their relationships to cortical neural activity, and quantify their characteristics and their underlying biophysical origins. BOLD signals have previously been robustly detected in gray matter (GM) in response to stimuli in a very large number of studies. In addition, correlations of signal fluctuations between cortical regions in a resting state have been analyzed to derive functional connectivity. However, whether such signals reliably arise in WM remains controversial, and their interpretation is unclear. We have previously shown that BOLD signals can be reliably detected in WM if appropriate detection and analysis methods are used, and that in a resting state they exhibit anisotropic temporal correlations that largely align with WM tracts. Multiple such lines of evidence converge to suggest that WM BOLD signals are related to intrinsic, function-dependent neural activity and are apparent only in tracts engaged in specific functions. However, the precise relationships between WM and corresponding GM signals have not been established, and neither the characteristics nor origins of the hemodynamic response function (HRF) of WM have been elucidated. We hypothesize that BOLD signal variations in WM tracts are directly related to corresponding variations in neural activity in GM volumes to which they connect and/or which share specific functional roles, and that further studies will provide a new basis for more fully integrating structural and functional aspects of neural organization. In the proposed research we will [1] demonstrate and measure the relationships between BOLD signals in WM tracts (identified using diffusion imaging) and GM volumes in response to parametric stimuli whose variations modulate the degree of neural activity in specific cortical areas; [2] measure and characterize the HRF in specific WM tracts using event-related fMRI, and modify conventional models of BOLD responses to explain and fit those data; [3] establish the biophysical basis of stimulus-evoked BOLD activations in white matter by comparing data from different imaging sequences and field strengths, and by measuring BOLD signals in the brains of non-human primates with and without an intravascular susceptibility contrast agent to separate contributions from changes in blood volume vs blood oxygenation. Overall, these studies will validate the nature of WM BOLD effects, demonstrate their relevance in neural processing, and provide a basis for future studies of functional changes in a broad range of WM- associated disorders as well as development and degeneration.

Summary / Abstract This is an application for funding to upgrade an existing 9.4 Tesla magnetic resonance imaging (MRI) and spectroscopy (MRS) system that has been in constant use for 14 years at Vanderbilt University for studies of non-human primates and larger rodents. The upgrade (a replacement console, including main computer, spectrometer and RF modules, RF and gradient amplifiers but not the magnet or gradient coils) is required (a) because after 14 years the spectrometer and electronics are no longer state-of-the-art and their performance limits ongoing research projects but also (b) the manufacturer (Agilent) is no longer (since October 2013) in the business of NMR or MRI, and will not provide upgrades, maintain hardware or support the system after 2020. The upgrade will ensure the continuing productivity of this important resource, and at the same time provide enhanced capabilities. This device will be used by at least 14 established investigators, all of whom are already experienced users of the 9.4T scanner, in a variety of research applications and training programs currently supported by 19 major grants. These research projects fall into 4 main categories: (1) MRI physics, the development of novel imaging biomarkers at high field, and of a greater understanding of the nature of the information provided, along with applications in small animals: (2) Cancer, and the development and applications of MRI and MRS for the study of tumor biology in animal models, including the development of more sensitive ways to assess novel treatments and treatment response: (3) Neuroscience, and the application of structural and functional MRI to studies of the architecture and functional organization of the brain and spine in non-human primates, as well as the action of novel pharmaceuticals: (4) Other applications including metabolic and infectious disorders, and the applications of advanced MR methods to studies of physiology and biochemistry in vivo. The projects of the 7 Major Users would require approximately 73% use of the instrument (1760 hours/yr) , the 7 Minor Users would require about 10% of the time, and the remaining time available would be available for exploratory research and new directions. Each of the projects will benefit from the advantages of imaging at 9.4T, including high signal to noise ratio (SNR), high spatial resolution, high spectral dispersion for CEST and MRS, and high sensitivity for detecting changes caused by specific contrast mechanisms such as BOLD. The scanner will be housed and managed within the Vanderbilt University Institute of Imaging Science, and will remain a primary research resource for a large number of experienced imaging scientists and trainees. The instrument will be supported by an established group of MRI experts and support staff. A comprehensive plan has been developed for the financial and technical support of the scanner as well as for its management and use, and the system is assured of strong institutional support and oversight.

Abstract / Summary This proposal aims to perform novel, secondary analyses on large archives of publicly-available fMRI studies in order to quantify the functional characteristics of white matter (WM) and their changes during normal aging and in the progression to Alzheimer?s Disease (AD). Blood oxygenation level dependent (BOLD) effects have been used to detect neural activity in grey matter (GM) for many years, but BOLD signals in WM have traditionally been ignored so they have not been considered in previous analyses. However, WM BOLD signals have been evaluated in relatively small numbers of healthy brains, and these studies have shown that WM shows robust, tract-specific BOLD changes in response to stimuli, WM exhibits inter-regional correlations in a resting state similar to those used to infer functional connectivity in cortex, and signal fluctuations within WM tracts in a resting state show strong correlations to specific GM cortical volumes engaged together in functional networks. We therefore propose to adapt the tools developed for analyzing GM connectivity and for diffusion imaging of WM to analyze the functional changes in WM with age in >7,900 imaging studies available publicly. In Aim 1, we will detect and characterize changes in WM functional networks with normal aging by analyzing subjects from the Baltimore Longitudinal Study of Aging (BLSA), the Open Access Series of Imaging Studies (OASIS-3) and the Alzheimer?s Disease Neuroimaging Initiative (ADNI). Neuroimaging studies of AD suggest that WM abnormalities exist at a preclinical stage of the disease, so detecting and quantifying altered WM function may be an important metric of functional changes in this disorder. In Aim 2 therefore we will measure alterations in WM functional networks in subjects enrolled in the ADNI, BLSA, and OASIS-3 databases. In both Aims we will also measure co-variations of WM connectivities with behavioral, clinical and genetic assessments to establish how WM functional metrics reflect behavior and cognition and change with increasing cognitive impairment. In Aim 3 we will extend the creation of atlases and machine learning from current studies of diffusion MRI to quantifying WM functional MRI by creating age-adjusted atlases of WM functional MRI properties to enable normative comparisons and provide canonical templates for both functional and structural connectivity network analyses. We will also apply data-driven deep learning to identify individual signatures of impairment on a whole-brain basis. A failure of white matter functional integrity is clearly implicated in aging and neurodegeneration. This proposal will develop new understandings of the functional changes in WM across the lifespan, identify pathological changes in WM function with AD, and create new data-driven tools for interpretation of WM fMRI.

Abstract This is an application to upgrade a 7 Tesla magnetic resonance imaging (MRI) and spectroscopy (MRS) system at Vanderbilt University that has been used for human subjects and large animal research for the past 13+ years. The upgrade (a replacement console, including computers, spectrometer and RF modules) is required (a) because after 13 years the spectrometer and electronics are no longer state-of-the-art and their performance limits ongoing research projects, and (b) the manufacturer (Philips) has developed new and improved hardware with more advanced digital technology that matches their main 3T products, and they will not be able to provide upgrades, maintenance or adequate support for the current system in the future. The upgrade will ensure the continuing productivity of this important resource, and at the same time provide enhanced capabilities. In the past 3 years alone the device has been used by over 20 different investigators across 47 projects. We have contributed over 75 publications to the literature in different areas. The high field system is used for research in 5 primary areas: [1] novel technical developments of imaging and spectroscopic methods for use at ultra-high fields; [2] studies of brain structure, organization and function in human subjects, for basic neuroscience and clinical applications in neurology, psychiatry and neurosurgery; [3] studies of the function, structure and disorders of the spine; [4] studies of brain structure and function in large non-human primates, including novel methods of neuromodulation; [5] imaging of sodium and multinuclear MRS studies of biochemistry and metabolism in vivo, with applications in metabolic disorders. The 7T MRI scanner at Vanderbilt is our flagship research platform. It was purchased for $7 million in 2006 when it was one of the first 10 such systems in the world. It is housed in 400 tons of steel that cost an additional $1 million. Since installation it has received several upgrades, including the addition of an 8 channel multi-transmitter system, and has worked well with relatively little down time. The projects of the 16 Major Users (33 different grants) would require approximately 74% use of the instrument (1480 hours/yr), the 5 Minor Users (7 grants) would require about 6% of the time, and the remaining time would be available for exploratory research and new directions. Each of the projects will benefit from the advantages of imaging at 7T, including high signal to noise ratio (SNR), high spatial resolution, high spectral dispersion for CEST and MRS, and high sensitivity for detecting changes caused by specific contrast mechanisms such as BOLD. The scanner is housed within the Vanderbilt University Institute of Imaging Science, has appropriate support spaces, and is used and supported by an established group of MRI experts and staff. A comprehensive plan has been developed for the financial and technical support of the scanner as well as for its management and use, and the system is assured of strong institutional support and oversight.