Kamil (Kâmil Uğurbil) Ugurbil - US grants

The general objective of the proposed research is to extend the use of high resolution nuclear magnetic resonance as a non-invasive, in vivo probe of cellular processes and utilize its capabilities to study several specific problems in cell metabolism and physiology. Proposed work will consist of the following studies. 1) Measurement of relaxation parameters T1, T2, and nuclear Overhauser effect (NOE) of 13C, 31P and 1H nuclei of NMR detectable metabolites in a variety of cell types ranging from prokaryotes (E. coli) to single cell eukaryotes (S. cerevicia), to mammalian tissue (perfused hearts and liver) where the relaxation mechanisms may be different due to different intracellular conditions; exploration of the utility of contemporary pulse sequences for the detection of 13C resonances, and the development of new pulsed techniques by which proton resonances of hydrogens bonded to 13C labeled carbons are selectively observed from cells. These efforts are aimed at improving the sensitivity and the detection limits of NMR, which is generally the limiting factor in the cellular applications of this technique. 2) Development of tissue culture systems for 31P, 13C and 1H NMR studies with particular emphasis on questions involving hormone effects, comparison of normal, oncogenically transformed, and other cell lines with disorders. 3) 13C and 1H NMR studies on carbon metabolism in methane producing anaerobe Methanosarcina barkeri for the purpose of understanding methane production by these anaerobes, and biodegradation of halogenated phenols which are highly toxic compounds used throughout the world and which are catabolized by bacteria. 4) 31P and 13C NMR studies on the effect of cardiotonic drugs (in particular ARL 15BS, MDL 19000205 and amrinon) on the energetics and metabolism of perfused guinea pig hearts and heart failure models to be prepared from these animals. 5) Studies of the long term effects of these drugs on the heart energetics and metabolism in normal animals and animals with heart failure using whole animals and 31P chemical shift imaging; it is also anticipated that this work, in collaboration with the Department of Cardiology, University of Minnesota, will be extended to other clinical studies using animal models.

oxidative phosphorylation; heart metabolism; myocardium; bioenergetics; myocardial ischemia /hypoxia; aerobic exercise; oxygen consumption; catecholamines; heart motion; heart circulation; high energy compound; glucose metabolism; coronary vasodilator; hemodynamics; reperfusion; coronary occlusion /thrombosis; heart pharmacology; adenosine triphosphate; creatine kinase; heart catheterization; biopsy; dogs; ultrasound blood flow measurement; nuclear magnetic resonance spectroscopy;

biomedical equipment resource; clinical biomedical equipment; oxygen consumption; adenosine triphosphate; creatine kinase; adenosinetriphosphatase; nucleotide metabolism; kidney transplantation; myoglobin; heart metabolism; heart disorder diagnosis; cyclosporines; bioenergetics; noninvasive diagnosis; myocardium; myocardial infarction; myocardial ischemia /hypoxia; congestive heart failure; hypertrophic myocardiopathy; heart function; heart pharmacology; renal toxin; liver transplantation; radiotracer; disease /disorder model; stable isotope diagnosis;

No Abstract Provided

myocardial ischemia /hypoxia; myocardium; nuclear magnetic resonance spectroscopy; oxygen consumption; adenosinetriphosphatase; magnetic resonance imaging; imaging /visualization /scanning; bioenergetics; electrophysiology; biotransformation; cardiography; radiotracer; dogs; tritium; disease /disorder model;

At the present time, the University of Minnesota in vivo NMR group has a 4.7 Tesla 40 cm bore imaging/spectroscopy system equipped with an Oxford magnet and a console manufactured by the Spectroscopy Imaging Systems (SIS) Company, Fremont, CA. This NMR system is used heavily and exclusively for seven NIH funded projects that are concerned with the development and biomedical applications of spatially localized in vivo NMR spectroscopy. Based on the needs of these seven NIH projects, matching funds are requested from the BRS Shared Instrumentation Grant Program to replace the magnet and the associated gradient set of the 4.7 Tesla / 40 cm instrument with a 7 Tesla / 33 cm bore system; a $600,000 request towards the acquisition,of this 7 Tesla/33 cm bore magnet and gradients has already been awarded in an NIH program project grant (2POl HL32427) which includes three of the seven projects that form the basis of this particular application. Beyond enhancing the research endeavors of the primary investigators utilizing in vivo NMR spectroscopy at the University of Minnesota, the availability of a 7 Tesla/ 33 cm system would represent a major advance in NMR spectroscopy applications in animal models in general, and would definitively provide the impetus and the means to drive this field forward beyond its present capabilities.

DESCRIPTION (provided by applicant): Center for Magnetic Resonance Research at the University of Minnesota is an interdepartmental and interdisciplinary research laboratory that has been funded as a Biotechnology Research Resource (BTRR) during the last nine years. The central research focus of this BTRR is development and improvement of methodologies and technologies for high magnetic resonance (MR) imaging and spectroscopy, and providing state-of-the-art instrumentation, expertise and infrastructure to enable the faculty, trainees and staff of several institutions in the USA and abroad to carry out basic and applied biomedical research that utilizes these unique high magnetic field (4 to 9.4 Tesla) capabilities. The general aim of this application is to seek continued support for this Biomedical Technology Research Resource so as to pursue new methodological and technical developments and maintain a National Research Resource with unique instrumentation and expertise that is not readily available elsewhere. A central and primary aim of the Core projects is to develop techniques for obtaining simultaneous information on aspects of organ function, perfusion, oxygen extraction, metabolism, and anatomy in humans non-invasively, using the unique advantages provided by high magnetic fields, such as the high signal-to-noise ratio, increased susceptibility effects associated with blood for imaging brain function, longer Tls for measurement of tissue perfusion, increased chemical-shift resolution for improved detection of neurochemicals, and the use of magnetic isotopes of biologically active atoms, such as O-17, which are not accessible easily at low magnetic fields due to their low gyromagnetic ratio. These techniques have been and will continue to be utilized to support a large community of NIH funded researchers working in neurosciences, functional brain mapping, brain metabolism, metabolic disorders, and cardiac pathology and bioenergetics.

The 3-D Fourier Series Window technique yields multi-voxel spectra from spatially localized regions of predetermined shape with minimal out-of-voxel contamination. Cylindrical voxels are utilized in this particular study, with localization first demonstrated in a phantom experiment. The method is then applied in vivo to noninvasively study the transmural distribution of 31P metabolites across the left ventricular wall of the myocardium in an intact canine model; high quality spectra are obtained from 1.4 ml voxels in about 15 to 30 minutes at 9.4 Tesla in the canine chest.

We have designed and constructed a preliminary 4T whole head volume array RF coil that works within our head gradient set. Previously, it has been demonstrated that substantial SNR gains are possible with a volume coil array consisting of shorter volume coils covering an extended FOV [38, 39] over a single coil covering the same FOV. We utilized this approach using a combination of two short quadrature birdcage coils to cover the whole human head. Applications such as single shot EPI which is routinely used in fMRI studies currently requires the use of the head gradient set in order to achieve sufficiently fast switching times at 4 T. Therefore, one of the requirements was to build such a coil within the confines of a head gradient set. The isolation between the quadrature ports of either coil was below -25 dB. This isolation was sufficient for imaging without further active preamplifier protection. The electromagnetic coupling between the coils could be adjusted to be below -18 dB at the feeding points. Load changes from subject to subject were found not to be critical in regard to coil decoupling. The necessary adjustments for tune and match from subject to subject was accomplished within minutes. Tune and match was easily adjusted for each birdcage coil separately thus also indicating minimal coil interactions. We obtained images to compare the SNR and homogeneity of the birdcage array coil with a high-pass birdcage coil. These images showed that when the subject was appropriately placed, Coil #1 covered the cerebellum, the brain stem and the lower part of the cerebral cortex and Coil #2 imaged the rest of brain. High sensitivity and homogeneity was observed in the combined images over the entire head and especially in the cerebral cortex, resulting in a maximal signal-to noise gain of up to 40% as compared with a 22 cm long high-pass birdcage even though the axially the FOV was substantially larger than then provided by the single high-pass birdcage. The axial homogeneity in the overlap area was excellent and comparable to that of a single birdcage coil.

Concurrent with the experimental demonstrations of fMRI, calculations and experiments evaluating the vascular origin of the BOLD effect were performed by our group. Calculations previously demonstrated that the BOLD phenomenon has two components, one dependent linearly and other quadratically on the main magnetic field magnitude (Bo) arising from macro-and microvasculature, respectively. Consistent with these theoretical and experimental studies, a study we performed in the last funding period demonstrated that the BOLD contrast-to-noise ratio was found to depend on magnetic field strength less than linearly in voxels containing vessels larger than the voxel itself and greater than linearly in voxels containing a mixture of capillaries and veins/venules with diameter less than that of the voxel. The experimental result in this study further demonstrates that a high magnetic field provides improved contrast for fMRI and more emphasis to more specific areas containing small vessels.

In response to the needs to acquire data with higher duty-cycles and wider bandwidths for EPI imaging than possible with our SIS Co./Varian console, and to add multiple channels for phased array detection we have already designed and implemented our own intermediate frequency (IF) digital receiver (DR). The IFDR satisfies these needs and additionally gives better filter performance and eliminates distortions and artifacts present in standard analog receivers due to the replacement of several analog components by digital signal processing (DSP). The IFDR goes beyond the capabilities of commercially available MR receivers particularly in the areas of data acquisition speed, DSP, and data I/O bandwidth.

functional magnetic resonance imaging; computer system hardware; biomedical equipment purchase;

Purchase of equipment.

DESCRIPTION (adapted from the applicant's abstract): Recent studies from the applicant's laboratory have suggested that in normal myocardium perfusion limits maximal ATP synthetic capacity, MVO2 and mechanical performance. Whether subsequent steps in the ATP synthetic process are also limiting is unclear. Whether maximal MVO2 and mechanical performance in the abnormal heart are also limited by ATP synthetic capacity is unknown. The objectives of the current proposal are to: 1) continue development of new techniques applicable to in vivo MRI and MRS studies; 2) use these new techniques to define further the rate limiting step in the ATP synthesis process that ultimately restricts maximal MVO2 in the normal heart; and 3) to use these same methods to examine the functional and bioenergetic responses of the remodeled (post-infarction) myocardium to basal and maximal workstates and to determine whether ATP synthetic capacity ultimately restricts maximal MVO2 in the remodeled heart. The applicant will examine the in vivo transmural responses of myocardial high energy phosphates, ventricular performance, blood flow, myocyte deoxymyoglobin saturation and MVO2 under baseline and maximal workstate conditions in normal pigs and pigs with post-infarction remodeling. These data will be correlated with myocyte morphometric data. Conventional physiological methods and magnetic resonance imaging and (spatially localized) magnetic resonance spectroscopy techniques will be employed; the latter provide a unique opportunity to study transmurally heterogeneous metabolic responses of normal and remodeled myocardium.

The primary aim of this proposal is to significantly expand the present capabilities of basic neuroscience research focused on human brain function by establishing a 7 Tesla/90 cm-bore NMR imaging/spectroscopy instrument at the Center for Magnetic Resonance Research (CMRR). Only recently has it been possible to develop the necessary instrumentation and methodology, explore the potential, and establish the advantages of higher fields to extract complementary functional and biochemical information and a significant part of that work was realized at the CMRR. The 7T/90 cm system will enable a major leap in these developments and provide a mechanism by which this unique instrumentation, spin- physics methodology, and expertise, are available to researchers in the USA and elsewhere. Unraveling the mysteries of the human brain represents one of the great challenges of modern biology. Recently developed Functional Magnetic Resonance Imaging (fMRI) method has provided a unique capability towards meeting this challenge. Further developments to improve sensitivity, spatial specificity, and spatial resolution, an extend the methodology to temporally resolved true single event related studies require higher neuronal activation, and significant increases in the magnitude of the inherently weak signal changes that are used in fMRI. In going to 7 Tesla, these combined gains are expected to catapult this methodology to a level that is significantly beyond what is currently available. Equally important are efforts relying on detection of key intracellular compounds in the human brain using NMR spectroscopy to investigate coupling between cellular bioenergetics and neuronal activity; however, additional gains in sensitivity and spectral resolution available at 7T are needed to make a significant impact on the biological problem.

The primary focus of cardiac research in this laboratory has ben the development of progressively more powerful magnetic resonance methodologies and their application to the investigation of myocardial bioenergetics and metabolism. The current proposal continues this strategy and is centered around the use of 1h NMR techniques to evaluate myocardial myoglobin deoxygenation in vivo for the first time, combined with 31 P NMR measurements of high energy phosphate compound levels using spatial localization to differentiation layers across the left ventricular wall. The latter is a necessary capability because of the well recognized transmural gradients of wall-stress, O2 utilization, and biochemical composition. The general biological questions to be examined concern the mechanisms of regulation of oxidative phosphorylation in normal myocardium in vivo at very high levels of energy expenditure, and the effect of post- ischemic myocardial stunning on this regulation. Specifically, we propose to establish the 1H NMR capability to monitor deoxy- and oxy-myoglobin in and across the left ventricular wall in situ by means of non-localized and transmurally localized differentiation in an open chest, instrumented canine model. Previous 1h NMR studies of myocardial myoglobin oxygenation have been performed in perfused rodent heart models. In vivo studies are crucial if physiologic regulation of O2 supply by the vasculature is to be taken into account and to permit proper interpretation of 31P NMR data obtained during physiological or pharmacological interventions. The transmurally differentiated Mb detection will be used together with our already well established, transmurally localized 31P spectroscopy approach to examine the specific biological questions of whether i) maximal workloads and myocardial oxygen consumptions rate attainable by normal in situ cardiac muscle are dictated by a limitation of oxygen and/or carbon substrate delivery to the mitochondria, and ii) such a limitation may be exacerbated by a transient ischemic result.

Funding for a "body" gradient set and its associated gradient and shim drivers are sought for improved performance for a 4 Tesla/90 cm MR instrument used for high magnetic field human spectroscopy and imaging research. 4 Tesla high field MR systems for human studies were introduced in 1991 for the first time in three different academic laboratories in the United States one of which was our lab, the Center for Magnetic Resonance Research (CMRR), University of Minnesota. Since then, rapid methodological developments in data acquisition and optimization demonstrated the usefulness of such high fields in biomedical research leading to ever increasing interest in these instruments as research tools. One of the major limitations of these high field instruments has been the performance of the gradients for spatial encoding and "shims" for homogenizing the magnetic field. All of these high-field instruments have so far been equipped with gradients that were originally designed for 1.5 Tesla clinical MR imagers; in addition, these gradient sets were early designs even for 1.5 Tesla instruments and do not possess improved design, manufacturing, and ultimately the performance that are becoming available in 1.5 Tesla systems. In addition, we have established a quantitative understanding of the stringent shimming requirements at high fields which permits us to define the shim performance criteria that are simply not met in gradient sets originally designed for 1.5 Tesla clinical imaging systems. If advantages that are provided by high magnetic fields are to be fully exploited, going to better gradient performance that also provide convenience of use and subject/patient comfort and tolerance is imperative. The proposed upgrade will impact a large body of NIH funded grants that focus on. developing and/or using high magnetic fields for biomedical research.

To date, owing to their wide availability,1.5T systems are used for the majority of fMRI studies although high-field (3T and 4T) systems have also been used. Conceptual considerations of BOLD mechanism predict a fundamental dependence on magnetic field strength and led to the suggestion that the sensitivity, contrast, and spatial specificity of the BOLD response to neural activity increase with the field strength. These predictions, however, have only been examined so far in a relatively few studies all based on animal models. While animal studies provide us with data that can elucidate the biophysics of fMRI in certain models, they are not necessarily fully applicable to the human brain BOLD fMRI. First, most animal studies are conducted under anesthesia, where the physiological parameters are different from that of awake human subjects. Second, the signal-to-noise ratio as well as spatial and temporal resolutions achievable with animals are much more than that achievable in humans, making the translation of animal results to humans inappropriate. Third, paradigms that can be applied to animal models are mostly limited to sensory stimulation. Fourth, the vascular architecture in animals differs from that in humans with respect to all vessels except capillaries. For these reasons, it is important to investigate fMRI in humans at ultra high magnetic fields to elucidate the field dependence of various attributes of fMRI and ascertain the advantages of high magnetic field. With the availability of a 7 Tesla whole-body imager,it is now possible to investigate these issues directly in the human brain for the first time. The overall goal of the present application is to investigate the characteristics of fMRI at ultra high magnetic fields and utilize these potential advantages for high resolution fMRI that can probe neuronal function at the millimeter to sub-millimeter spatial scale. As ultrahigh field human systems are still in their experimental stage, technical development is needed to make use of its capabilities. To realize the anticipated increase in sensitivity and spatial specificity, it isnecessary to develop methodology for high-resolution fMRI at ultrahigh fields. In addition, as physiological noise may scale with the signal in the data, become dominant, and mitigate the advantages of high field, it is important to understand it and to develop improved methods to reduce it. Thus the first aim of this project will focus on these two technical aspects. Our second aim will then investigate the field dependence of sensitivity and specificity and how these issues affect spatial and temporal resolutions. For these studies we propose to focus on high resolution fMRI of brain regions rather than the whole brain at this stage since the latter goal presents an additional set of challenges that are beyond the scope of this application. With these considerations in mind, our specific aims are 1) technical development and understanding of signal fluctuations in fMRI at high fields and 2) characterization of the BOLD response at ultrahigh magnetic field with high spatial and temporal resolution.

DESCRIPTION (provided by applicant): The aim of this application is to locate a state-of-the-art 9.4T/65cm bore MRI system at the University of Minnesota's Center for Magnetic Resonance Research (CMRR) for non-human primate and human MR imaging and spectroscopy studies of brain function and neurochemistry. This system will be the first of its kind, providing for the first time, a 9.4T field magnitude with a sufficiently large bore size to conduct human and non-human primate studies. No other system at this field strength with such a bore size exists. This system will become a shared resource for CMRR collaborators at the Wisconsin Regional Primate Research Center (WRPR) in Madison, Wisconsin, and will serve the needs of numerous investigators from several institutions located in the Midwest and the East coast. With its in-house staff of fifty five investigators and support staff, the expertise in high field magnetic resonance research, and support as a Biotechnology Research Resource (BTRR) by NIH for "High Field Magnetic Resonance Imaging and Spectroscopy", the CMRR is an ideal facility to support the shared instrument and its users. The proposed 9.4T system will have a Varian Associates, Inc. lnova console and a Magnex Scientific, Inc. superconducting magnet with 7 G/cm shielded gradients and high-order shims. The magnet will have a 65 cm inside diameter that will step to a gradient/shim coil inside diameter of 40cm. The gradient set will serve as a "head" gradient for human studies, while providing large access for non-human primate work including awake monkeys. With four receiver channels and two transmitter channels, this system will be capable of multi-nuclear spectroscopy from 12 MHz to 400 MHz with full second-channel decoupling capability. The echo-planar imaging (EPI) compatible gradients will make it possible to perform dynamic fMRl studies. Signal-to-noise and spectroscopic resolution at 9.4T has been demonstrated to be twice that of standard 4.7T animal research systems for 1H nuclei and 4 times for the lower gyromagnetic ratio 170 nucleus. Overall, this non-human primate and human primate dedicated NMR system will provide state-of-the-art performance and capability for imaging of laboratory animals and humans for the first time at such high magnetic fields.

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community

Animals; BOLD response; CRISP; Cats; Cell Communication and Signaling; Cell Signaling; Complex; Computer Retrieval of Information on Scientific Projects Database; Count; Dependence; Dissociation; Domestic Cats; Feline Species; Felis catus; Felis domestica; Felis domesticus; Felis sylvestris catus; Frequencies (time pattern); Frequency; Functional Magnetic Resonance Imaging; Funding; Grant; Image; Institution; Intracellular Communication and Signaling; Investigators; MRI, Functional; Magnetic Resonance Imaging, Functional; Mammals, Cats; Measures; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous; Range; Relative; Relative (related person); Research; Research Personnel; Research Resources; Researchers; Resources; Signal Transduction; Signal Transduction Systems; Signaling; Site; Source; Spike Potential; Stimulus; United States National Institutes of Health; Visual Cortex; analog; biological signal transduction; blood oxygenation level dependent response; experiment; experimental research; experimental study; fMRI; hemodynamics; imaging; neural; relating to nervous system; research study; response; visual cortical

DESCRIPTION: (provided by applicant): In the armamentarium of techniques available for contemporary biomedical research carried out with humans at the basic, translational, and clinical level, magnetic resonance (MR) methods have become critical and indispensible, often providing non-invasive measurement capabilities that are simply unavailable from alternative approaches. The central aim of this Biotechnology Research Center (BTRC) grant is to significantly advance such MR based measurement capabilities and their biomedical applications in humans by: 1) developing novel image acquisition and reconstruction technologies and engineering solutions through five TRD (Technology Research and Development) projects, and 2) enabling a large number of Collaborative and Service projects to acquire advanced structural, functional, and physiological information to investigate human organ function in health and disease, targeting both human brain and the abdominal organs. This central aim will be pursued with a focus on high (3 and 4 Tesla) and particularly ultrahigh (7 Tesla and higher) magnetic fields, which provide numerous advantages but also pose several significant technological challenges that must be overcome. This is a unique feature and a particular strength of this BTRC; ultrahigh field MR and numerous accompanying methods for human studies were pioneered in this BTRC, yielding previously unavailable detection sensitivity and precision. This BTRC is also home to some of the most advanced, unique and rare high field MR instrumentation in the world. Collectively, these unique instruments and the proposed methodological developments are expected to be transformative for MR technology and its applications.

DESCRIPTION (provided by applicant): The specific acquisition desired in this application is a eight-channel radiofrequency (RF) transmit front-end capable of generating channel-specific, user- defined RF pulse patterns to drive independent transmit elements in a multichannel transmit or transmit/receive RF array-coil at 7Tesla. The proposed hardware will be incorporated into an existing 7Tesla instrument located within the University of Minnesota's Center for Magnetic Resonance Research (CMRR). This 7 Tesla is the central instrument in the NIH-funded Biotechnology Research Resource Center (P41 RR08079) and the Neuroscience Blueprint Center Core (P30 NS057091) located at the CMRR, and, in this capacity, supports a large number of NIH funded investigators and projects both within and outside of the University of Minnesota. As such, the proposed upgrade will impact a large number of users. This request is based on the fact that imaging in general and magnetic resonance (MR) imaging in particular has evolved to become an indispensible part of contemporary basic and clinical biomedical research, central to discoveries in a large number of disciplines. In this development, recent work has established that ultrahigh magnetic fields (7 Tesla) provide numerous advantages and are emerging at the forefront of this methodology. However, conventional means of exciting MR signals are suboptimal in the brain and simply do not work in the human body at 7 Tesla where the RF wavelength at the proton resonance frequency is ~12 cm and, thus, smaller than the dimensions of the human head or body. In this regime, the radiofrequency (RF) field generated by conventional single, channel transmit systems, is highly non-uniform and power consumptive for most biomedical applications. Solutions to this problem depend on the ability to dynamically control the RF excitation field over a number of degrees of freedom. The proposed instrument is capable of achieving this and is indispensible in the optimal use of the 7 Tesla platforms on human studies. PUBLIC HEALTH RELEVANCE: Magnetic resonance imaging (MRI) is one of the most powerful tools in the armamentarium of techniques employed to investigate the biomedical complexities of the human body in health and disease. This proposal requests funds for instrumentation that will provide a significant enhancement in MRI by enabling the use of higher magnetic fields, which provide significant gains provided that challenges associated with them, can be solved.

DESCRIPTION (provided by applicant): In the last two decades, a plethora of magnetic resonance (MR) techniques, such as functional magnetic resonance imaging (fMRI), perfusion imaging, MR spectroscopy, etc. have come to play an indispensable role in biomedical research, as well as in clinical practice. In our laboratory, the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota, the evolution of such methods has been intricately tied with the development of high field MR, starting with 4 Tesla (T) in 1990 (one of first three installed at about the same time) and 7 Tesla in 1999 (the first such system), ultimately leading to the rapidly growing interest in 7 T both in the research community and the manufacturers of clinical MR platforms. Based on the dramatic improvements that can be realized at the ultrahigh fields due to combined gains in signal-to-noise ratio (SNR) and contrast mechanisms, it is now anticipated that imaging at this magnetic field will also impact clinical practice and that such a "clinical" scanner is inevitable. The aim of this proposal is to explore these gains further and push the boundaries of MR research further by establishing a 10.5 Tesla (~450 MHz proton frequency) MR imaging and spectroscopy instrument with sufficiently large bore size (83 cm clear bore) to perform studies on the human brain as well as the human torso and extremities. 10.5 T represents a significant increase over the current, most commonly available ultrahigh field platform, i.e. 7 Tesla. No such instrument currently exists in the world. An 11.7 T, 68 cm bore (~500 MHz) "head only" system is planned for NIH intramural research and a major effort in France aims to develop a similar system based on a larger bore magnet. The rational for our request is based on the demonstration, largely coming from our laboratory, that (i) ultrahigh fields provide unique information that is not available at lower magnetic fields, (ii) such information can be obtained not only in the human brain but, with appropriate technological developments, in the human torso and extremities as well, and (iii) such information is useful both for basic biomedical and translational research as well as for clinical medicine. If successful, this HEI grant will place this advanced instrument in a laboratory that is funded as a Biotechnology Research Center (BTRC) for high field MR research and a laboratory with appropriate interdisciplinary expertise and infrastructure to maximally utilize it. Recognizing this, the University of Minnesota will provide the funds to acquire the magnet and build the necessary space to install it. Funds are requested in this HEI grant for the rest of the equipment to convert the magnet into an integrated MR system and for the appropriate RF and magnetic field shielding. ) PUBLIC HEALTH RELEVANCE: Since its discovery, magnetic resonance imaging (MRI) has come to play an indispensible role in clinical medicine as a diagnostic tool and in biomedical research aimed at understanding normal organ functions and mechanisms underlying human diseases. This proposal aims to push the boundaries of MR technology further by establishing a 10.5 Tesla MR imaging and spectroscopy instrument with sufficiently large bore size (83 cm clear bore) to perform studies on the human body. This instrument will be first of its kind in the world and the highest field available for research in both the human brain as well as the human torso and extremities.

DESCRIPTION (provided by applicant): This project will characterize adult human brain circuitry, including its variability and its relation to behavior and genetics. To achieve this ambitious objective, a broad-based multi-institutional consortium of distinguished investigators will acquire cutting-edge neuroimaging data in 1,200 healthy adult humans along with behavioral performance data and blood samples for genotyping. The main cohort of subjects will be twins plus non-twin siblings - a strategy that enables powerful analyses of heritability and genetic underpinnings of specific brain circuits. Comprehensive connectivity maps will be generated for each individual and for population averages using sophisticated data analysis methods. This human connectome will be expressed relative to functional subdivisions (parcels) defined by connectivity and by classical architectonic methods. Data from these maps will reveal fundamental aspects of brain network organization. A powerful, user-friendly informatics platform will be implemented to facilitate the management, analysis, visualization, and sharing of these rich and complex datasets. Because these tools and datasets will have Immediate and long range potential to influence neuroscience research in health and disease, extensive outreach efforts are planned for promoting their widespread awareness and usage. The imaging modalities include three types of magnetic resonance imaging: (i) diffusion imaging using HARDI methods to map structural connectivity; (ii) resting-state fMRI (R-fMRI) to reveal maps of functional connectivity; (iii) task-fMRI (T-fMRI) to reveal brain activation patterns associated with a broad set of behavioral tasks. Magneto-encephalography (MEG) and also EEG will be used to characterize dynamic patterns of neural activity that can be related to structural and functional connectivity maps. Imaging will benefit from a customized 3T scanner developed for this project and ultimately installed at Washington University, a new 7T scanner at the University of Minnesota, and improved pulse sequences and custom coils to be implemented during the project's optimization phase. By scanning all subjects at 3T and subsets at 7T and with MEG, the complementary strengths of each imaging modality will be utilized and the overall impact of the data collection and analysis strategy will be maximized. Consortium members have contributed greatly to the recent progress in data acquisition and analysis strategies that make the Human Connectome Project technically feasible. Major additional advances anticipated during the project's optimization phase will lead to unprecedented fidelity of the structural and functional connectivity maps to be obtained during the production phase.

This Integrative Graduate Education and Research Traineeship (IGERT) award supports the development of a multi-disciplinary, integrative graduate education and training program in NeuroEngineering (NE) at the University of Minnesota at Twin Cities. Intellectual Merit: The purpose of this program is to train doctoral students to develop the skills to revolutionize technologies for interfacing with the brain and advance the fundamental understanding of neuroscience processes that arise when interfacing with and modulating the brain.

Broader impacts include the development of a multi-disciplinary training program that blurs the boundary between neuroscientists and engineers, thus enabling a new generation of scientists to competently and confidently take on the grand challenges in the interdisciplinary field of NeuroEngineering. The NE program includes major research themes in decoding brain signals, modulating brain dynamics, and bi-directional brain interfacing. The program is a "degree-plus" model in which pre-doctoral students are admitted to one of the participating graduate programs (Biomedical Engineering, Electrical Engineering, Mechanical Engineering, and Neuroscience), and are trained through a series of hands-on, modular neuroengineering courses. All NE Fellows will immerse themselves in a lab outside their major in the summer of their first year, engage in multiple lab rotations, and participate in at least one clinical lab rotation, summer internship at a neurotechnology company, or summer international research experience. NE Fellows will have co-advisors beginning in their first year, one from the engineering sciences and one from the basic or clinical neurosciences. The training program incorporates several outreach efforts to recruit women and underrepresented minorities, provide outreach to K-12 and industry, and train NE Fellows to be effective communicators.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

MULTIMODALITY CORE PI: Geoff Ghose, PhD; co-PI Bin He, PhD Because of our expertise in high field MR, the CMRR offers experimental resources that are uniquely suited to pursue high-resolution in-vivo studies on spatial and temporal scales that have been demonstrated by classic neuroscience methods to be relevant for the understanding of brain function and disease. The aim of this core is to serve and further develop research efforts by NINDS investigators by offering multimodal capabilities and associated support in which traditional neuroscience methodologies can be readily combined with the MR research capabilities of the CMRR. This Core aims to support both human and animal model studies.

The general aim of this proposal is to continue the successful NINDS Institutional Center Cores (P30 NS076408) at the Center for Magnetic Resonance Research (CMRR), University of Minnesota (UMN). These Cores offer state-of-the-art instrumentation, advanced technology, and unique expertise for biomedical imaging in CMRR so as to provide cutting edge resources and facilities to investigators who have existing NINDS-funded research projects serving the NINDS mission through ?basic, translational, and clinical research on the normal and diseased nervous system?. In the last two and a half decades, magnetic resonance (MR) techniques have evolved to become indispensable in studies of the brain in health and disease by providing otherwise unavailable measurement capabilities in humans and animal models. The optimal use of these techniques requires advanced instrumentation, unique expertise, and complex auxiliary capabilities such as animal surgery, large-scale data and image processing, and complementary measurements employing classical techniques (e.g., electrophysiology and histology). Access to these facilities and methodologies, especially at the cutting-edge, is virtually impossible in individual labs. The proposed NINDS Center Cores will provide and encourage access to these advanced technologies and associated unique expertise to amplify NINDS funded neuroscience research. These aims will be accomplished through three scientific Cores: 1. MR Image Acquisition and Engineering Core (to provide application specific pulse sequences, and hardware, such as RF coils) (PI: Pierre-Francois van de Moortele; co-PI Gulin Oz) 2. MR Data Analysis and Visualization Core (to provide applications specific image and spectroscopic analysis tools and support) (PI: Christophe Lenglet; co-PI Noam Harel) 3. Multimodality Core (to support complementary non-imaging measurement capabilities) (PI: Geoff Ghose) The overall aim of this grant is to provide this access within the multidisciplinary, and interactive research environment of CMRR, so as to enrich the effectiveness of and promote new research directions in a large number of ongoing NINDS funded research projects.

1. HIGH AND ULTRAHIGH FIELD IMAGE ACQUISITION AND ENGINEERING PI: Pierre-Francois van de Moortlele, PhD Core Aims The long-term goal of this core is to provide the means to enhance, broaden and accelerate a large array of ambitious neuroscience research projects that are increasingly utilizing high (3 and 4T) and ultrahigh (7T and above) field MR Imaging instruments and novel image acquisition and reconstruction techniques to investigate brain structure and function. Multiple studies have now amply demonstrated that MRI at higher magnetic fields can provide significant advantages in signal-to-noise ratio (SNR), spatial resolution, anatomical delineation, and anatomical and functional contrast. When combined with the appropriate imaging methods, these gains can be transformative in basic and translational neuroscience projects. However, access to such advanced capabilities by neuroscience researchers is virtually impossible outside the context of a collaborative and multidisciplinary relationship, especially (but not only) when instrumentation at the cutting-edge of the field, such as those operating at high (HF) and ultrahigh fields (UHF), and advanced, asof- yet commercially unavailable imaging methods are employed. The aim of this core is to provide the necessary support and infrastructure that will allow a large community of NINDS funded investigators to utilize advanced imaging methodologies and instrumentation in CMRR where there exists a large parallel effort (funded by other sources) on instrumentation and methodology development.

IMAGE AND SPECTROSCOPY ANALYSIS AND VISUALIZATION CORE PI: Christophe Lenglet, PhD; co-PI: Noam Harel, PhD This Core will provide advanced analysis tools and resources for a variety of neuroimaging modalities including structural MRI, High Angular Resolution Diffusion Imaging (HARDI), Diffusion Spectroscopic Imaging (DSI), functional MRI (fMRI), intrinsic relaxation parameter imaging, MR spectroscopy (MRS), as well as Positron Emission Tomography (PET) and Computed Tomography (CT). The unique needs of each of these modalities will be served through shared computing equipment, software and expert personnel in the Core. Additionally, the Core will provide support for multi-modality image analysis. Image reconstruction, analysis and visualization require sophisticated mathematical modeling and computational resources. The overall goal of this Core is to provide such unique resources for human and animal neuroimaging research. They will enable individuals to generate high-quality images from high (3 and 4T) and ultrahigh (7T and higher) field MR scanners and to efficiently analyze them through state-of-the-art methods.

2. MOLECULAR IMAGING CORE PI: Michael Garwood, PhD; co-PI: Jerry Froelich MD; Co-I Gulin Oz CORE AIM Magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) are two major modalities of molecular imaging, which allow direct assessment of metabolite and tracer concentrations in brain in vivo. They are critically important in studies of neurochemistry, brain function and perfusion, and can provide surrogate markers to detect brain diseases, to monitor disease progression, and to evaluate the effectiveness of novel therapies. With MRS, the richness of the biochemical information and the accuracy of metabolite quantification are strongly linked to spectral quality. In this regard, the ultrahigh field MRI/MRS systems in the CMRR, particulariy the new 16.4 T rodent capable system, the 9.4 T animal system with [13]C DNP hyperpolarizer, the 7T human systems, and the future 10.5 T human system, offer major advantages. In particular, they provide superior signal-to-noise ratio (SNR) and spectral resolution, for improved reproducibility in the detection and quantification of brain metabolites. In addition, brain scans with human PET/CT, microPET/CT, and Neuro SPECT are now available in the recently expanded CMRR.

PROJECT SUMMARY Our knowledge of signal processing in various parts of the human brain has been heavily influenced by non- invasive functional magnetic resonance imaging (fMRI) experiments. FMRI infers the location and selectivity of neural activity from vascular signals. However, brain circuits are much more complex than regional differences in neuronal selectivity. Specifically, the largest part of the brain (neocortex) accounts for up to 80% of the brain volume and is divided into six distinct layers. Specific computations, e.g., local processing vs. feedforward inputs vs. vs. feedback inputs, are done in specific cortical laminae. Thus, if high-resolution layer-specific fMRI is shown to reflect the repertoire of neural computations performed across these cortical layers, it would be an invaluable refinement to non-invasive imaging. However, despite the widespread usage of low-resolution fMRI, a detailed understanding of how neural activity generates vascular responses remains unknown. The goal of this project is to elucidate the link between neural and vascular signals across laminae by combining two-photon imaging of neural and vascular responses with ultra-high-field (UHF) fMRI. Experiments will use sensory visual stimuli that induce layer-specific responses. In cat primary visual cortex (V1), which has a functional architecture (e.g., maps for stimulus orientation) similar to human V1, we will measure neural activity (synaptic and spiking) with single-cell resolution together with vascular signals (blood flow, blood volume, and oxygenation) in individual vessels across the entire cortical thickness. We will also perform UHF lamina-specific fMRI in cat (9.4 and16.4 T) and human (7 and 10.5 T) V1 to relate fMRI signals to the single- vessel responses. Lastly, we will develop a model to relate lamina-specific vascular signals to neural activity. In Aim 1, we test the hypothesis that vascular signals selective for stimulus orientation are present in cortical layers 2/3 (and 5/6) while untuned responses occur in layer 4 and pial vessels. Grating visual stimuli will be used, while varying orientation and eye preference (ocular dominance) systematically. Since binocular integration is stronger outside layer 4, eye preference vascular signals should be most prominent in layer 4. In Aim 2, we will test the hypothesis that in any given cortical lamina, glutamate release in regions around an individual blood vessel best accounts for the selectivity of vascular responses compared to spiking activity?in terms of the preferred stimulus orientation and tuning width. Aim 3 is to build a computational model to determine effective minimum voxel size for BOLD fMRI. The model will be tested against simultaneously measured vascular and neural activity to natural scene stimuli using two-photon imaging. If the source signals at the finest spatial scales have laminar specificity, we can correlate laminar-specific fMRI signals to differences in neural processing. To our knowledge, this is the first study that brings together such a wide repertoire of approaches into a single project to understand the neural and laminar basis of fMRI.

? DESCRIPTION (provided by applicant): The major technological and analytical advances in human brain imaging achieved as part of the Human Connectome Projects (HCP) enable examination of structural and functional brain connectivity at unprecedented levels of spatial and temporal resolution. This information is proving invaluable for enhancing our understanding of normative variation in young adult brain connectivity. It is now timely to use the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain changes during the aging process. Using state-of-the art HCP imaging approaches will allow investigators to push our currently limited understanding of normative brain aging to new levels. We propose an effort involving a consortium of five sites (Massachusetts General Hospital, University of California at Los Angeles, University of Minnesota, Washington University in St. Louis, and Oxford University), with extensive complementary expertise in human brain imaging and aging and including many investigators associated with the original adult and pilot lifespan HCP efforts. This synergistic integration of advances from the MGH and WU-MINN-OXFORD HCPs with cutting-edge expertise in aging provides an unprecedented opportunity to advance our understanding of the normative changes in human brain connectivity with aging. Aim 1 will be to optimize existing HCP Lifespan Pilot project protocols to respect practical constraints in studying adults over a wide age range, including the very old (80+ years). Aim 2 will be to collect high quality neuroimaging, behavioral, and other datasets on 1200 individuals in the age range of 36 - 100+ years, using matched protocols across sites. This will enable robust cross-sectional analyses of age-related changes in network properties including metrics of connectivity, network integrity, response properties during tasks, and behavior. Aim 3 will be to collect and analyze longitudinal data on a subset of 300 individuals in three understudied and scientifically interesting groups: ages 36-44 (when late maturational and early aging processes may co-occur); ages 45-59 (perimenopausal, when rapid hormonal changes can affect cognition and the brain); and ages 80 - 100+ (the `very old', whose brains may reflect a `healthy survivor' state). The information gained relating to these important periods will enhance our understanding of how important phenomena such as hormonal changes affect the brain and will provide insights into factors that enable cognitively intact function into advanced aging. Aim 4 will capitalize on our success in sharing data in the Human Connectome Project (HCP), and will use these established tools, platforms, and procedures to make this data publicly available through the Connectome Coordination Facility.

ABSTRACT: The strategic plan of the NIH's BRAIN Initiative (BRAIN 2025: A scientific Vision) calls for transformative technological developments with MRI to achieve ?submillimeter spatial resolution descriptions of neuronal activity, functional and structural connectivity, and network analysis in the human brain through advances in instrumentation, data acquisition and analysis techniques?. The primary aim of this grant application is specifically to undertake such technological developments. We plan to usher in the next generation MR instrumentation, and data acquisition and image reconstruction methods in order to reach and span currently unavailable spatial scales in human brain studies, going from neuronal ensembles composed of few thousand neurons to whole brain function and structural connectivity. The focus of the proposed work will be resting state- and task- or stimulus-based functional imaging (fMRI), and diffusion imaging (dMRI) methods for tractography and white-matter microstructure determination. We present a strategy, based on ample preliminary data, to develop and implement unique and novel gradients, B0 shims, RF coils, image acquisition and reconstruction methods, and previously unavailable 10.5 Tesla ultrahigh magnetic field. As a result of the cumulative gains from the proposed technologies, we anticipate an order of magnitude or more reduction in voxel volumes, thus reaching and even exceeding the resolution targets set forth in the BRAIN Initiative strategic plan. Using this new capability, we also plan to generate a publicly available database that will enable the most complete and accurate description of the functional and structural connections among gray matter locations in the human brain to date, and facilitate advanced computational modeling of how information is encoded by neural populations in the human brain. The proposed developments will be carried out by a consortium composed of investigators from the University of Minnesota Center for Magnetic Resonance Research (CMRR), Stanford University Lucas Center for Imaging, Penn State Center for NMR Research, NYU Center for Biomedical Imaging and Oxford University; together they bring to this project unique experience and track record of accomplishments in high resolution functional and diffusion imaging, ultrahigh magnetic field technology and applications, RF pulse and pulse sequence development, multichannel transmit technology, gradient design and construction, manufacturing and use of novel dielectric materials, RF coil design and construction, and image reconstruction and post- processing.

PROJECT SUMMARY (ADMINISTRATION) The Biotechnology Research Center delivering ?Technology to realize the full potential of UHF MRI? has an Administrative Core that coordinates all BTRC related activities, including the development of ultrahigh field (UHF) magnetic resonance (MR) and optical imaging/MR technologies, their dissemination, and training of researchers in their use. The co-PIs of this core are Drs. Kamil Ugurbil and Greg Metzger. Dr. Ugurbil is an expert in UHF MR methodology and instrumentation with longstanding experience managing multi-center collaborations. Dr. Metzger is an expert in UHF MR technology and its application with experience developing and managing interdisciplinary research programs. Daily operations of the BTRC are the responsibility of the Co-PIs in close interaction with the other PIs of the Technology Research and Development (TRD) projects (Drs. Adriany and Akçakaya). The full group of BTRC PIs, together with PIs from the P30 Neuroscience Center Core located in the Center for Magnetic Resonance Research (CMRR), comprises the Operations Committee, which meets biweekly. The main goal of this committee is to assure that access to and use of the BTRC resources is accomplished in a fair and transparent manner including ensuring the push-pull relationship with the Collaborative Projects and a path for access to the technology developments for the Service Projects. The task of the Operations Committee is facilitated by operating procedures and tools which help manage requests and prioritize projects, including both 1) a web-based interface for requesting access to Center resources and 2) faculty and staff support to guide users in the process. Additional infrastructure in the Center is available to ensure projects can be carried out in a safe and successful manner including the following: Pre-IRB Review System, Incidental Findings Review System, 3T Operations Committee, Safety Committee and a Magnet Operator Training. The progress of the BTRC is reviewed yearly by the External Advisory Committee (EAC) comprised of experts in the fields of our TRDs. The primary role of the EAC will be to annually review our scientific progress and our progress in collaboration, service, training, and dissemination goals. The results from the meeting will be incorporated into a yearly report drafted by the EAC, which will be submitted to NIBIB as part of the annual progress report. Through the activities of the administrative core and the consistent and substantive institutional support from the University of Minnesota, our long-term goal is the establishment of a national biotechnology research resource for the development of unique technologies that advance biomedical research and discovery.

ABSTRACT: The strategic plan of the NIH's BRAIN Initiative (BRAIN 2025: A scientific Vision) calls for transformative technological developments with MRI to achieve ?submillimeter spatial resolution descriptions of neuronal activity, functional and structural connectivity, and network analysis in the human brain through advances in instrumentation, data acquisition and analysis techniques?. The primary aim of this grant application is specifically to undertake such technological developments. We plan to usher in the next generation MR instrumentation, and data acquisition and image reconstruction methods in order to reach and span currently unavailable spatial scales in human brain studies, going from neuronal ensembles composed of few thousand neurons to whole brain function and structural connectivity. The focus of the proposed work will be resting state- and task- or stimulus-based functional imaging (fMRI), and diffusion imaging (dMRI) methods for tractography and white-matter microstructure determination. We present a strategy, based on ample preliminary data, to develop and implement unique and novel gradients, B0 shims, RF coils, image acquisition and reconstruction methods, and previously unavailable 10.5 Tesla ultrahigh magnetic field. As a result of the cumulative gains from the proposed technologies, we anticipate an order of magnitude or more reduction in voxel volumes, thus reaching and even exceeding the resolution targets set forth in the BRAIN Initiative strategic plan. Using this new capability, we also plan to generate a publicly available database that will enable the most complete and accurate description of the functional and structural connections among gray matter locations in the human brain to date, and facilitate advanced computational modeling of how information is encoded by neural populations in the human brain. The proposed developments will be carried out by a consortium composed of investigators from the University of Minnesota Center for Magnetic Resonance Research (CMRR), Stanford University Lucas Center for Imaging, Penn State Center for NMR Research, NYU Center for Biomedical Imaging and Oxford University; together they bring to this project unique experience and track record of accomplishments in high resolution functional and diffusion imaging, ultrahigh magnetic field technology and applications, RF pulse and pulse sequence development, multichannel transmit technology, gradient design and construction, manufacturing and use of novel dielectric materials, RF coil design and construction, and image reconstruction and post- processing.

OVERALL ABSTRACT The Center for Magnetic Resonance Research (CMRR) has pioneered many of the MR methods that are critical in contemporary biomedical research including (but not limited to) the introduction of UHF instrumentation and accompanying techniques that overcome its challenges, accelerated MR imaging approaches, and many of the methods used to obtain biochemical information in vivo using spectroscopy and multinuclear capabilities. To continue the tradition of innovation, the long term goal of this Center proposal is to establish a national resource for enabling ultrahigh field (UHF, mostly 7T and above), magnetic resonance imaging (MRI) technologies to advance biomedical research and discovery. Towards building this P41 center, several technical research and development (TRD) projects are proposed that will work synergistically to realize the potential of our unique imaging resources. TRD1 involves the development of a multimodal imaging platform allowing simultaneous optical imaging, an invasive technology capable of visualizing neuronal activity at the single neuron and synapse level, with non-invasive MRI methods which provide high resolution functional MRI and connectivity data over the entire brain but at a coarser spatiotemporal resolution. This platform will provide unprecedented opportunities for detailed studies of brain function underlying behavior and inform future human studies using MRI alone. TRD2 focuses on establishing a sensitive molecular imaging platform combining novel systems solutions and advanced strategies to perform multinuclear MRI spectroscopy and imaging studies. This system will provide unparalleled sensitivity to probe molecular parameters to characterize tissue through molecular dynamics, spatial distributions of functional metabolic parameters and advanced multinuclear studies. TRD3 develops reconstruction strategies supporting highly accelerated high-resolution imaging approaches while incorporating methods to reduce the impact of physiologic motion and noise. These reconstruction methods advance the field by overcoming what otherwise would be limiting factors with respect to achievable temporal and spatial resolutions. TRD4 provides critical engineering solutions addressing both 1) radiofrequency (RF) coil (i.e. antennae) designs and safety for sensitive high resolution imaging at UHF without which the systems conceived of in TRD1 and TRD2 could not be realized and 2) methods to image around implants by minimizing heating and artifacts which if not addressed would limit the access of the UHF imaging to a large section of the population. As described, these projects can tackle the fundamental challenges of UHF. Only when these challenges are addressed can we develop the new approaches to truly advance basic and clinical translational research. In fact it is exactly this cycle of development and discovery that inspired, then justified, the spending of time and resources to develop, build and site the 10.5T system at our center. While the 10.5T scanner is at the center of the proposed developments, the impact of this Center on biomedical research will extend 7T and below as well as to fields beyond MRI (cognitive science, neuroscience, senescence, musculoskeletal disorders, neurological disorder, cancer among others).

Project Summary/Abstract Brain function is mediated by hierarchical local and long-range circuits organized across multiple spatial scales. Bridging and spanning these scales of organization is essential for understanding brain function and ultimately dysfunction; however, no single existing technology can accomplish this daunting task. Human brain activity and connectivity can be studied with non-invasive magnetic resonance (MR) methods that can cover the entire brain. However, the spatiotemporal resolution and fidelity to neuronal activity is limited because of the intervening neurovascular coupling that is the source of the MR mapping signals. These limitations can be overcome if MR resolutions and fidelity can be improved so as to reduce the heterogeneity of the responses within an MR voxel and, in addition, the MR method is combined with other techniques that simultaneously report on neuronal and/or neurovascular responses, ideally sampling the activity within one or more MR voxels at the single neuron, synapse or vessel level. Besides interrogating the link between neuronal activity and the MR based functional mapping signals, the complementary nature of such a combination of techniques would provide the means for bridging the multiple spatial and temporal scales, going from the cellular and synaptic level to coordinated activity over billions of neurons spanning large parts of the brain, if not the entire brain. This TRD approaches this problem by proposing to develop i) advanced MR methods for imaging brain function and connectivity at unprecedented spatial resolution using very high magnetic fields, ii) combining such MR measurements with simultaneous measurements of multi-photon recordings of neural signals (at single cell and/or synapse level) and corresponding hemodynamic responses at the level of individual arterioles, capillaries and venules, within the environment of an ultrahigh field (UHF) magnet on the same animal and under the same experimental conditions. Because of the invasive nature of the optical methods the combined experiments can only be performed in animal models while the MR techniques to be developed would be applicable to human imaging as well.

PROJECT SUMMARY/ABSTRACT The aim of this proposal is to replace the currently dysfunctional, unsupported and discontinued ?Varian? console (due to termination of Varian as a company) on a unique 16.4 Tesla/26 cm bore Instrument dedicated to small to medium size animal model studies at the Center for Magnetic Resonance Research (CMRR). Currently CMRR possesses a unique 16.4T/26 cm horizontal bore instrument which was funded by an $2M HEI grant in 2007/2008 and substantial matching funds (~ $10M) from the University of Minnesota in order to expand the boundaries of magnetic resonance (MR) methodologies and their applications in biomedical research using small to medium-sized animals (e.g. rodents to cat). This unique NMR instrument is the highest magnetic field available for animal model studies in the U.S.A. Only one instrument (located in Neurospin in France) operating at 17.2T exceeds it in magnetic field strength for small to medium size animal model studies (a 21 Tesla vertical bore system large enough for mouse and rat studies but not medium size animals exists in the Magnet lab in the USA). CMRR?s 16.4T system was meant to play a crucial role in a large number of projects on animal models conducted within our past Biotechnology Research Center (BTRC, P41 EB015894) and the NINDS Institutional Center Core Grants to Support Neuroscience Research (P30 NS076408), as well as multiple large NIH funded projects supported by R01 and other grant mechanisms. It is still slated for a critical role in our recently funded BTRC P41 EB02706, and competitively renewed P30 grants (2P30 NS076408) both of which support a multitude of projects, as well as in numerous currently funded R01 and U01 grants. However, instrument has been and currently still is dysfunctional for 1H studies, and has also reached its limits of its viability for all other nuclei due the disappearance of the console manufacturer Varian. This instrument was purchased from Varian Inc. However, shortly after that instrument was established, Varian was purchased by Agilent Technologies in 2010. Because of the transition, problems with 1H nuclei remained unsolved though the instrument worked well for less demanding low gamma nuclei. In 2013 Agilent decided to terminate the MR Imaging business completely and approximately a year later closed down all NMR activities, thus leaving essentially all Varian users, including us, in a very difficult position. Several problems on the instrument after its delivery (e.g. gradient driver instabilities, SNR losses in 1H frequency) remained unresolved as many Varian engineers were laid off and a commitment and the ability to fix these problems in Agilent vanished. Already many Varian users migrated to the consoles provided mainly by Bruker. Therefore, we are pursuing in this application what must inevitably happen due to the disappearance of Varian as a manufacturer and service organization; namely replacing it with an integrated and supported console from Bruker.

Summary The last decade ushered in amazing advances in neuroimaging due to transformative developments in magnetic resonance and optical imaging techniques as well as in computational and modeling tools. A common thread in these advances is their multi-disciplinary nature, requiring collaborations among medical researchers, engineers, physicists, mathematicians, and data scientists, among many others. In order to continue the pace of technical advances in neuroimaging and to exploit their unique capabilities for brain research and medical applications, it is critical to train the next generation of neuroimaging specialists in a setting 1) with an abundance of state-of-the-art tools, 2) with a programmatic interest in developing novel neuroimaging technologies and biomedical applications, and 3) where trainees can carry out groundbreaking research under multi-disciplinary mentorship. The University of Minnesota (UMN) has an excellent tradition of training neuroimaging postdocs in its Medical School and its College of Science & Engineering. It is also the home of major, world-renowned efforts in neuroimaging technology development and novel biomedical applications of neuroimaging. The proposed Minnesota Neuroimaging Postdoctoral Training Grant aims to give 14 postdoctoral fellows ? at least 4 of whom will be from communities under-represented in STEM fields ? multi-disciplinary skills in neuroimaging technology development and advanced biomedical applications, guidance in career development, and social and networking support through intense two-year neuroimaging fellowships at UMN. Each fellow's primary research will be conducted on a multi-disciplinary project that combines their background with another field with the express goal of developing new neuroimaging technologies. Each fellow will be co-mentored by two faculty selected from the 40+ participating faculty in this grant: one that will directly supervise the research project, and one that represents a core area related to the research project. Fellows will take at least two courses to broaden their skillset and prepare for either an academic or industry research career. They will participate in an Annual Retreat and twice-monthly seminars that will cover research and career development topics such as responsible conduct of research, scientific rigor and reproducibility, grant writing, and other key subjects. They will also participate in UMN's numerous neuroscience conferences, symposia, and workshops, along with well-established UMN outreach programs to high schoolers and undergraduates from communities under-represented in STEM fields. The program will be managed by an Executive Board that represents the diversity of the participating faculty across the Medical School and the College of Science & Engineering. Management plans include a rigorous, ongoing evaluation process that incorporates an external Advisory Board and the University of Minnesota's internal research and assessment services.

ABSTRACT The pathophysiology of Alzheimer?s disease involves a plethora of structural and functional abnormalities of multiple brain structures and related circuits, including neurodegeneration of the hippocampus, a critical hub responsible for memory and executive function. While progress has been made in documenting the hallmarks of the disease?s pathophysiology, the sequence of events that lead to hippocampus atrophy, loss of memory, and loss of executive function with disease progression remain insufficiently characterized due to the lack of in- vivo markers sensitive to the process of neurodegeneration. To address this unmet need our goal is to establish rotating frame MRI relaxation mapping based on Frequency Swept (FS) pulses, adiabatic T1? and RAFFn, as novel, non-invasive biomarkers of neurodegeneration and demyelination. This goal is supported by the fact that the rotation frame relaxation parameters that will be investigated, allow us to probe slow motional components of the spectral density function unlike standard free-precession MRI metrics. This slow motional regime is most relevant to characterize multiple biological processes at the molecular and cellular levels in tissue as we and others have demonstrated in other pathologies. As such, our overarching hypothesis is that adiabatic T1? will serve as an early marker of neural degeneration of the hippocampus, while RAFFn will be able to detect demyelination, and both markers will correlate with neural network dysfunction at different stages of Alzheimer?s disease, as detected by resting state functional MRI. Three specific aims will be pursued to investigate this hypothesis: 1) optimization of parameters for obtaining high-resolution mapping of rotating frame MRI metrics from hippocampal subregions and layers, 2) identify rotating frame MRI markers of brain tissue abnormalities in a rat model of Alzheimer?s disease as compared to age-matched wile-type rats and 3) uncover the Alzheimer?s disease pathophysiological substrates that best correlate with the novel rotating frame MRI biomarkers, as revealed by resting-state fMRI, histology and spatial genomics. Accomplishing these aims will establish the potential of rotating frame MRI markers as novel biomarkers of neurodegeneration in Alzheimer?s disease by extending technical developments proposed in the parent grant. Spatial genomic analysis will allow us to identify the molecular basis of the MRI outcomes, thus providing an invaluable validation needed for optimizing therapies, monitoring treatment response and supporting subsequent applications in humans.