Bruce Rosen - US grants

The first nuclear magnetic resonance (NMR) images were produced in 1973; in the ensuing years significant advances have been made in instrumentation and technique. Concurrent with developments in imaging technology NMR spectroscopic techniques have been applied with increasing frequency to study biological systems. The goal of this grant is to further develop and evaluate techniques which acquire proton spectroscopic (chemical shift) information within an NMR image. Specifically, efforts will focus on two primary aims. First, the ability to measure signal intensity and relaxation times of the two primary contributors to the proton spectra, lipid and water, will be tested using three chemical shift imaging techniques. Phantom data will be used to verify theoretical predictions of S/N and technique bias. Rat models of hepatic steatosis with and without the concomitant hepatitis will be used to validate these observations in vivo, and to compare the sensitivity of conventional NMR techniques to the three chemical shift imaging methods using multicomponent relaxation time measurements. Studies will then be extended to the investigation of human liver pathology. In order to facilitate rapid transfer of information to the clinical environment, studies of human bone marrow will be made in parallel with animal liver studies. These will first focus on patterns of normal bone marrow development. A pilot study of bone marrow in human leukemias will then be carried out, testing the ability of multicomponent measurements to characterize normal and abnormal marrow elements. The second specific aim of this study is to use proton chemical shift imaging techniques to map cerebral lactate during global and focal hypoxic insult. The sensitivity, precision and accuracy of lactate measurements will be determined in phantoms, evaluating techniques of both water and lipid suppression. Non-imaging experiments in rats will be carried out to evaluate system linearity in vivo, and tissue lactate relaxation times will be determined over a range of concentrations. A cat brain model of global hypoxia, temporally stabalized, will be imaged, with brain lactate levels determined biochemically compared to lactate image signal intensity. This model wil be extended in studies of focal ischemic insult. Pilot studies of lactate accumulation in humans will also be carried out, investigating stroke and CNS tumor patients.

The goal of the proposed research is to develop and validate magnetic resonance (MR) methods that can sensitively detect and characterize tissue perfusion. Preliminary data in our laboratory has demonstrated the feasibility of utilizing both contrast and non-contrast techniques. We will therefore explore three approaches: 1) In studies of the heart with Gd-DTPA, we will apply a comparmental kinetic model, similar to those used in nuclear medicine, to relate measured MR image intensity changes following injection of the agent to myocardial blood flow and the volume of distribution of the agent. The method will be validated in a canine model of normal and partially stenosed myocardium, and then used to test the feasibility of using MR measurements with Gd-DTPA and the vasodilator dipyridamole as an MR stress test for evaluating coronary artery disease. 2) In brain studies with Gd-DTPA, we will optimize techniques for measuring both the T1 relaxation effects, and the more pronounced transient susceptibility-induced signal loss on T2-weighted images. The physical basis of the latter effect will be clarified by phantom experiments and theroretical modeling. Preliminary data suggests that the susceptibility effect is correlated with cerebral blood flow (CBF), and we will determine the relation between both of these effects and CBF and cerebral blood volume (CBV) measured with radioactive tracers. Animal experiments will be performed in a rat model of global physiological variation and a cat model of middle cerebral artery occlusion. 3) Methods for brain imaging based on the intrinsic effects of motion on the MR signal, which require no contrast agent, will be developed to provide accurate measures of diffusion and restricted diffusion, and to separate the effects of diffusion and perfusion with a perfusion sensitive pulse sequence. These methods will be tested in phantoms and in the same animal models as in the brain Gd-DTPA experiments. The brain imaging methods will be validated in human subjects in stroke, neoplasia and degenerative dementia by direct comparison with positron emission tomography (PET) maps of CBF and CBV. Sensitivity and specificity of these methods for lesion detection and characterization will also be compared with that of conventional T1- and T2-weighted imaging.

Noninvasive angiography with magnetic resonance has recently been demonstrated in our laboratory. By manipulating the inherent sensitivity of MR to proton motion, blood flow generates its own contrast. The projective format provides images of the vascular tree that resemble conventional Roentgen angiograms. Preliminary results demonstrate high resolution vascular images. Flow volume quantitation has also been demonstrated. This work proposes to extend, validate and apply these novel techniques. Parameters that affect both image quality and flow quantitation will initially be investigated in-vitro. Results will be used in an iterative fashion to refine these sequences. Validation of these techniques will proceed in animal models of abdominal aortic aneurysm (AAA) and iliofemoral occlusive disease. Qualitative and quantitative MR results will be compared with contrast angiography and with invasive measures of flow volume. Studies will then be obtained in selected patients with AAA and iliofemoral occlusive disease. Similar qualitative and quantitative comparisons will be made which will assist in the development of appropriate clinical MR angiographic protocols. Finally, a prospective study will be performed comparing contrast angiography with optimized MR angiographic techniques. It is anticipated that MR angiography will develop into a valuable diagnostic tool that may obviate the need for more invasive procedures.

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This proposal requests partial support for the purchase of a 3T whole body MR imaging-spectroscopy system. The hospital and the NMR program will provide the additional funding and long term support for this dedicated research instrument. As part of the MGH-NMR Center, this system will be a resource to the community of PHS-supported biomedical researchers at the MGH managed by the Internal Advisory Committee as outlined by Division of Research Resources in the program announcement. The scope of the MGH-NMR Center, which is largely funded through PHS grants, has expanded to include functional MR imaging and in vivo spectroscopy. Initial studies have enabled the development of novel MR approaches (including functional brain mapping, measurements of oxygen consumption and cell volume fraction as well as receptor and metabolite mapping) that have been applied to important biomedical problems (including alzheimer's and Huntington's Diseases, atheroma, cancer and ischemia) resulting in unique physiological (photic stimulation changes in blood volume to the occipital gray matter) and pathology (elevated lactate in Huntington's Disease) data. While these data are exciting, the capabilities of the available NMR instrumentation do not allow PHS researchers to adequately address new questions resulting from this research. All 14 projects will benefit from the increase in signal-to-noise (improvement in spatial and temporal resolution) provided by the proposed 3.0 T system. Individual projects will be enhanced by increases in spectral resolution and susceptibility contrast. These enhancements are particularly relevant to the susceptibility effects exploited by the brain imaging projects where the functional unit, the column, is just below the spatial resolution set by signal-to-noise at 1.5T. The requested instrument will serve as a hardware and software platform for the development of specialized pulse sequences and data processing to support the growing sophistication of the funded experiments. Through considerable experience in all areas of spectroscopy and functional imaging from theory, to implementation, to clinical applications, the personnel of the MGH-NMR center are well qualified to fully exploit the expanded potentials of the new device. The proposed equipment will be dedicated to research activities and will not be used for routine clinical studies. An award of this high field spectroscopy and imaging instrument will greatly enhance PHS-sponsored work at the MGH.

This is an application for a Program Project to study the basic human neuroscience of cocaine action. We propose a coherent and highly integrated group of studies based on functional magnetic resonance imaging (fMRI) of human subjects and animal models. The basic scientific goals of the study are to (1) understand the circuitry in humans that underlies cocaine induced euphoria, withdrawal dysphoria and cocaine- conditioned craving, (2) to investigate differences in regional brain activation by cocaine in nondependent versus dependent users. In order to take full advantage of the strengths of fMRI, one aspect of the program involves technical development of this tool, optimizing its ability to image cortical and subcortical structures hypothesized to play key roles in the human brain reward circuitry. Animal models are used in the program because they are necessary to interpret the biological significance of human fMRI data and to relate it well validated molecular models of cocaine-induced neural activation.

The hypothesis that motivates the Children's Hospital, Boston, Learning Disabilities Research Center (LDRC) is that neurodevelopmental mechanisms supporting temporal information processing are specifically disordered in learning disabled children. The basic approach to investigating this hypothesis is to use a variety of psychophysical, neuropsychological, and neurophysiological probes with children classified as LD and to compare the results of such probes with a normative sample, and, more particularly, among the LD children themselves. It is the belief of the LDRC that data from these measures will permit the subgrouping of LD children in a way that is more reflective of different underlying neurophysiological deficits that, via various mechanisms, lead to the diagnosis of LD. One of the most powerful tools now available for doing non-invasive neurophysiological research with humans is functional Magnetic Resonance Imaging (fMRI). Project V will apply this technology to the study of the various subgroups of LD and non-LD children supplied and characterized by Projects I-IV. The initial purpose of Project V is to examine the activity of children's brains as they are performing the tasks of Project I. The goal is to seek underlying neurophysiological distinctions that will reflect the subgroupings proposed from Project I. As the program continues, tasks from Projects III and IV will also be adapted to the context of fMRI. Specifically, this project will: develop techniques for obtaining high quality functional Magnetic Resonance Imaging (fMRI) data from children; adapt the testing procedures proposed in Project I (low level information processing (LLIP)), Project III (neurobehavioral assessment), and Project IV (EEG), to the environment of fMRI; develop fMRI procedures to enhance MR's effective spatial and temporal resolution in the context of presenting the LLIP tasks of Project I to children; use fMRI to examine brain function of a substantial subset of the subject pool using tasks from Projects I, llI, and IV as adapted to fMRI; test proposed subgroups of LD subjects as derived by Projects I-IV; and seek such subgroups based on the fMRI data itself.

This research seeks to demonstrate and validate exogenous agent susceptibility and other intrinsic NMR contrast mechanisms for the in vivo assessment of active tumor neovascularity and the response to anti-angiogenic therapy. During the current funding cycle, we have demonstrated our ability to produce maps of cerebral blood volume (CBV) in humans. Using our understanding of susceptibility contrast mechanisms, developed in concert with Project 3 of this PPG, our data now support the hypotheses previously proposed that maps of brain and tumor blood volume can be generated, and that these maps are highly correlated with tumor malignancy, metabolic activity and ultimate clinical outcome. While these results are consistent with recent data on the role of tumor angiogenesis on tumor growth, simple maps of regional CBV, while promising, leave many of the most interesting questions regarding the non-invasive assessment of tumor microvascular proliferation unanswered. For example, recent post mortem and in-vivo animal work has demonstrated that the tumor vascular bed is characterized by significant changes in vessel morphology and physiology. Using first pass and equilibrium contrast agent approaches, mismatches in CBV and blood flow (FBF) in abnormal vessels will be assessed. Combined with novel MR measures of vessel size and density (developed in concert with Project 3), and MR techniques sensitive to the vascular endothelial permeability and tumor cell volume fraction developed concurrently during the previous funding cycle, a more complete picture of tumor angiogenesis will be obtained. The approach will be validated in animal cancer models of new vessel growth using vascular staining and casting techniques along with quantitative autoradiography. These techniques will also be applied to humans with gliomas, validated using PET and stereotactic biopsy quantitative histology, and applied to the problem of surveillance for malignant dedifferention. In addition, these techniques will be used to study the direct physiological consequences of treatment with the promising new class of therapeutics, the anti-angiogenic agents, and their role in monitoring therapeutic effect will be evaluated in animal models and in a pilot human trial Such studies are especially relevant in humans where little direct data on mechanism of action for these drugs exists. By providing a quantitative regional picture of the tumor microvascular bed, this research should enhance the characterization of tumors and choice of therapies in patients with brain and other systemic cancers.

craving; cocaine; behavioral habituation /sensitization; drug addiction; brain mapping; psychopharmacology; neurobiology; drug withdrawal; brain metabolism; clinical trials; functional magnetic resonance imaging; behavioral /social science research tag; human subject; clinical research;

The proposed work is part of the MGH, East Charlestown Program Project to the NIDA. Preliminary research has shown that cocaine induced changes in regional cerebral blood volume (rCBV), as measured by functional magnetic resonance imaging (fMRI), are more sustained in rats with a history of cocaine self-administration than in drug naive animals (i.e. rats that have performed for an equal amount of time on a food-reinforced behavior). The purpose of the investigation proposed here is to test the hypothesis that this sustained response in chronic animals correlates with an increase in the magnitude and duration of dopamine release in limbic structures of chronic animals. A second goal is to examine the hypotheses that different patterns of change in rCBV will be associated with the administration of dopamine D1 (SKF 81297, SKF 38393) and D2 (7-OH DPAT) receptor agonists to chronic as compared to naive animals. Finally, the hypothesis will be assessed that administration of non-selective serotonin (5-HT) receptor antagonists (methiothepin) and of selective 5-HT/1b/d partial agonists (GR 127935) alone and in combination with cocaine will produce distinct alterations in rCBV in chronic and naive rats. The animals will be prepared and trained at the laboratory of Behavioral Pharmacology, BU School of Medicine and then transported to the fMRI Laboratory at the Charlestown-MGH Laboratories. Use of fMRI measures of rCBV provides better time resolution of drug induced changes than do other imaging techniques. The results of this study will help to establish how chronic cocaine self- administration alters regulation by dopaminergic and serotonergic mechanisms of regional brain function over time.

This is a competing renewal submission for Project 1 of the NIDA Program Project "FMRI of Cocaine Action". The objective of this project is to investigate the brain reward circuitry mediating cocaine response the regional activation of brain reward circuitry in response to acute cocaine infusion are consistent across subjects. This work further suggests a dissociation of brain region s active during euphoria and during craving. Specifically, we find that the nucleus accumbens, basal forebrain, amygdala and ventral tegmentum consistently show distinct changes in fMRI signal that correlate with euphoria and craving in response to cocaine. The function of each of these regions with regard to brain reward is complex; presumably, these regions interact to produce discrete aspects of cocaine addiction such as euphoria, craving, expectancy, and cognitive choice for self-administration. In this Project we propose to investigate the role of each of these brain regions during cocaine-induced euphoria and craving. Specific Aim #1 is designed to evaluate the stability of the fMRI response to cocaine infusions in cocaine-dependent subjects. Experiments will focus on producing euphoria and craving, and test the hypothesis that reward circuitry will demonstrate consistent activation over time, a reproducible dose response, and rapid tolerance coordinated with subjective ratings during serial closely-spaced cocaine infusions. Specific Aim #2 will investigate the function of explicit cognitive and reward prediction processes on the fMRI response to cocaine infusion. Specifically, we will study the impact of reward expectancy and of decision-making for self- administration on fMRI response. In Specific Aim #3 we will evaluate the specificity of reward circuitry by comparing the fMRI pattern of brain activation and euphoric response in the same subjects following infusion of cocaine and the short-acting, mu opioid agonist remifentanil. Our core hypothesis for the proposed experiments is that distinct temporal patterns of events in brain reward circuitry, and other regions associated with reward, mediate cocaine-specific behavioral responses. These experiments will allow us to determine the roles of specific sub-cortical structures that mediate brain reward and underlie cocaine-induced euphoria and craving, thus significantly improving our understanding of the mechanisms maintaining cocaine dependence.

The Scientific Core is intended to serve as a central resource for the development and distribution of rat models of both focal and global ischemia and assessment of both physiological (blood flow, volume) and tissue outcome measures using histochemical and MRI techniques. Scientific Core will support component projects by Drs. Bonventre- Koroshetz, Moskowitz, Huang, Finklestein-Beal.

DESCRIPTION (provided by applicant): This P41 Biotechnology Resource Grant application seeks renewed support for our successful efforts to develop and apply innovative neuroimaging technologies within the highly integrated multimodal framework of the Center for Functional Neuroimaging Technologies (CFNT). The overall goal of this established NIBIB Biomedical Technology Resource Center (BTRC) is to provide advanced technology resources to more closely examine, and thus better understand, the human brain in health and disease. To this end, we seek to develop new techniques and advance existing technologies to acquire and analyze functional images of the working brain, with unprecedented physiological precision and spatiotemporal resolution, and to deploy these innovative tools to promote investigation of complex neuroscientific questions. Through coordinated research and development, collaborative research, service use, training and dissemination activities, our BTRC has built a standard of excellence in developing, sharing, and supporting the use of multimodal imaging tools that have consistently advanced capabilities for research that spans many basic science and clinical domains. Central to this effort are our four Technology Research and Development (TRD) projects to improve and extend techniques for non-invasive magnetic resonance image analysis (Project 1) and acquisition (Project 2), electromagnetic source imaging (Project 3), and optical neuroimaging (Project 4). Directly motivating the Aims of these TRD projects is a strong network of Collaborative Projects, which both challenge the TRDs to continue to innovate the next-generation neuroimaging tools, and reciprocally, employ the new tools we develop to drive their own research forward in new directions. Another essential element in this framework is the extensive application of our resources by a wide and diverse Service Users community. Finally, the TRDs, Collaborative and Service Projects contribute to the BTRC's Training and Dissemination mission, which additionally includes multiple dedicated Fellowships and Workshops, strong web presense, and important industrial partnerships, providing multiple channels to share the knowledge needed to apply the tools we develop with the scientific community locally, nationally, and internationally.

The explosion of fMRI-based neuroscience experiments point to the great need in the neuroscience community for reliable, freely repeatable, reproducible and non-invasive methods to study the human brain. Despite the technical challenge of performing fMRI experiments on "clinical" fMRI systems, the general availability of these systems and low risk associated with performing the studies has drawn a new generation of brain researchers to MR techniques. However, the difficulty and limitations of the existing state-of-the-art is readily (and usually quickly appreciated by most users who venture into the field. The core technical development of the proposed research is a set of interrelated projects that seek to create new multimodal methods for exploring brain function with MR imaging. These seek, both individually and collectively, to significantly extend many of the limitations of current brain mapping techniques: difficulty in comparing between regions of the brain and between brains of subjects, inflexibility of stimulus design and ambiguity of temporal data analysis, limited temporal resolution of functional information, and limited accessibility and portability of many current brain mapping technologies. We propose four technical projects to meet these challenges. In the first, we seek to improve the methods to unwarp the complex convolutions of the brain to create a more systematic 2D view of the cortex. In the second, we seek to develop new technologies for encoding and analyzing functional MRI data more flexibly and robustly. In the third, we seek to combine functional MR data with electrical recordings (EEG and MEG) in order to create anew high temporal and spatial resolution image of brain function. In the fourth project we focus on the development and validation of near infra-red diffuse optical tomography for the assessment of brain function. The resource will work interactively with collaborative investigators who will help the resource expand its technology and provide services to scientists in many disciplines. While the techniques focus primarily on brain imaging, they are considerably more broadly applicable to other parts of the body. The Regional Resource will provide training for students, fellows and staff scientists, and will advance the field of functional imaging through active dissemination of new technologies and results.

DESCRIPTION (provided by applicant): Project 1 aims to identify the brain networks influenced by acupuncture and to explore the interactions among those brain regions in both healthy subjects and in patients with major depressive disorder (MDD). We hypothesize that the limbic system and default mode network (DMN) constitute major pathways of acupuncture action. Our studies on healthy adults have demonstrated that acupuncture is associated with extensive deactivation in a network of limbic-paralimbic-neocortical brain regions closely related to emotion, cognition, autonomic function and sensory processing. We have also discovered that the brain regions that make up the DMN overlap with the limbic-paralimbic-neocortical regions influenced by acupuncture. The renewal of our CERC will allow us to extend our studies on healthy subjects and translate our findings to MDD. MDD is a highly prevalent mood disorder that can be significantly disabling and a burden to economy, and is known to involve dysfunction of the limbic system. Treatment is problematic and recurrences are common. Several clinical studies suggest that acupuncture may be a safe and economical alternative treatment for depression. Our fMRI studies on healthy subjects demonstrate that acupuncture has prominent modulatory effects on the brain regions that are involved in MDD. We will apply fMRI to explore the possible presence of subsystems in the DMN and LPNN (limbic-paralimbic neocortical network) by comparing the central effects of acupuncture with those of cognitive task and tactile stimulation in healthy subjects. We hypothesize that the temporo-spatial characteristics of acupuncture effects on the DMN and LPNN will overlap for different tasks, but that the preferential spatial distribution will differ. We will compare the effects of these external stimuli on the functional and effective connectivity of these networks. Our studies in healthy subjects will pave the way to studies involving patients with MDD, in whom we will examine the DMN and LPNN responses to facial expressions of fear and anger and the influence of acupuncture compared to healthy controls. We will also explore the effects of acupuncture on the functional and effective connectivity of these circuits in MDD, and correlate possible changes in mood and peripheral autonomic functions with the central effects of acupuncture by fMRI. By demonstrating scientific evidence of acupuncture's beneficial effects on intrinsic regulatory brain organization, the investigation will help to promote the integration of this ancient treatment into modern medical practice.

DESCRIPTION (provided by applicant) Recent studies have indicated that training-induced cortical plasticity may offer promising opportunities for the remediation of several different neurological conditions, such as stroke-induced movement disorders, dystonia, and dyslexia. However, extremely intensive training has been required, and has yielded results that, although promising, fall far short of a full cure. For this reason, there has been much interest in attempts to enhance cortical plasticity, including the use of noradrenergic drugs such as amphetamine in stroke-rehabilitation, and disinhibition of motor cortex in healthy subjects using ischemic nerve block. The study proposed here will investigate a novel approach, exploiting a newly available opportunity to apply plasticity-enhancing results from the animal literature to studies in humans. Experiments in animals have shown that cortical plasticity can be greatly enhanced by increasing the levels of the neurotransmitter acetylcholine (ACh). New drugs, known as cholinesterase inhibitors, that safely and effectively increase ACh levels in humans have recently been developed and FDA-approved. The specific drug that we propose to use is galantharnine hydrobromide (trade name Reminyl). The effect of the drug on cortical plasticity will be assessed using both visual psychophysics and fMR1. The psychophysical measure will be the rate at which the subjects learn to more accurately perform a simple visual perceptual learning task: learning to discriminate the orientation of a grating. The hypothesis to be tested is that learning of the visual task that takes place under the influence of the drug will proceed more quickly than learning that is paired with a placebo. Functional MRI will be used to assess the effect of the drug on cortical plasticity, by comparing the pre-training versus post-training brain activation changes that are caused by learning the visual task while on the drug against those caused by learning the task on placebo. If the novel method of enhancing plasticity that is proposed here should turn out to be successful, then there could be a wide range of potential clinical and practical applications.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Technological advances in imaging have revolutionized the biomedical investigation of illness. The tremendous potential that this methodology brings to advancing diagnostic and prognostic capabilities and in treatment of illnesses has as yet remained largely an unfulfilled promise. This potential has been limited by a number of technological impediments that could be in large part overcome by the availability of a federated imaging database and the attendant infrastructure. Specifically, the ability to conduct clinical imaging studies across multiple sites, to analyze imaging data with the most powerful software regardless of development site, and to test new hypotheses on large collections of subjects with well characterized image and clinical data would have a demonstrable and positive impact on progress in this field. The Morphometry BIRN (mBIRN), established in October 2001, has made substantial progress in the development of this national infrastructure to develop a data and computational network based on a federated data acquisition and database across seven sites in the service of facilitating multi-site neuroanatomic analysis. Standardized structural MRI image acquisition protocols have been developed and implemented that demonstrably reduce initial sources of inter-site variance. Data structure, transmission, storage and querying aspects of the federated database have been implemented. In this continuation of the mBIRN efforts, we propose three broad areas of work: [unreadable] 1) continuing structural MRI acquisition optimization, calibration and validation to include T2 and DTI; 2) translation of site specific state-of-the-art image analysis, visualization and machine learning technologies to work in the federated, multi-site BIRN environment; and 3) extension of data management and database query capabilities to include additional imaging modalities, clinical disorders and individualized human genetic covariates. These broad areas of work will come together in through key collaborations that will ensure utilization promotion by facilitating data entry into the federated database and creation of database incentive functionality. Our participating sites include MGH (PI), BWH, UCI, Duke, UCLA, UCSD, John Hopkins, and newly added Washington University and MIT. We have made a concerted effort to bridge the gap that can exist between biomedical and computational sciences by recruiting to our group leaders in both of these domains. Our efforts will be coordinated with those of the entire BIRN consortium in order to insure that acquisition and database functionality, and application-based disorder queries are interoperable across sites and designed to advance the capabilities to further knowledge and understanding of health and disease. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School (MGH/MIT/HMS) Athinoula A. Martinos Center for Biomedical Imaging is a world leading biomedical imaging research center. The mission of the Center is to develop and apply innovative biomedical imaging technologies to improve understanding of the pathophysiology and treatment of disease, and as a window to the function of the mind and brain. The success and increasing importance of our multimodal-imaging integration effort especially has motivated a phase of capital equipment expansion to increase the breadth of our imaging capabilities and extend them to investigate a wider range of biomedical questions. We have recently added magnetoencephalography (MEG) and Optical Imaging to our extensive NMR program. We have now begun to extend our complement of physiological imaging modalities to include Positron Emission Tomography (PET) because of its importance as a molecular and pharmacological imaging tool and the new scientific opportunities afforded by the integration of PET with our other imaging modalities. As part of our commitment to bringing PET to the Martinos Center, funding has been secured for the purchase of two PET imaging systems. The MGH has committed the space and a significant portion of the necessary resources to expand the Martinos Center to include a PET facility. An NCRR Extramural Facilities Construction Project grant will fund the remainder of the construction and siting costs for the facility. The longstanding expertise of the Radiology Department PET Program will ensure that facility is launched and operated expediently and proficiently. The aim of the current proposal is to obtain partial funding for the purchase of a General Electric (GE) PETtrace Radiotracer Production System, including self-shielded negative ion cyclotron and radiochemistry modules to support PET imaging at the Martinos Center. The proposed cyclotron and radiochemistry modules will be an important resource for currently funded and future neuropharmacological and molecular imaging research initiatives. With this instrument and our complete PET imaging facility, the Martinos Center will be able to provide, under one roof, the most advanced biomedical imaging tools available. The instrument will support and enhance the imaging activities of our NCRR Regional Resources (the Center for Functional Neuroimaging Technologies and the MGH/MIT GCRC), our NCI sponsored Center for Molecular Imaging Research and Small Animal Imaging Resource, and the many other PHS supported programs at the MGH, in the greater Boston area, and our national and international collaborations. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The Martinos Center for Biomedical Imaging is a leading imaging resource located at the Massachusetts General Hospital. The mission of the Center is to develop and apply innovative biomedical imaging technologies to improve understanding of the pathophysiology and treatment of disease, and as a window to the function of the mind and brain. The Center provides state-of-the-art imaging technologies including MRI, MEG, PET, optical imaging, and advanced image-processing capabilities to hundreds of investigators worldwide. While the Center currently operates two 3 Tesla MRI systems (Siemens MAGNETOM Allegra and Trio), the recent explosion in the use of high field MRI for functional brain mapping has led to a demand for these resources that exceeds our present ability to accommodate. Our 3T systems are now shared by more than seventy investigators whose productivity is greatly diminished by the insufficient availability of imaging time. The goal of this proposal is to obtain partial funding for a Siemens MAGNETOM 'TIM' Trio 3 Tesla MR system for the Martinos Center resource. The proposed system will alleviate overcrowding on the present systems allowing currently funded investigators sufficient imaging time to accomplish their research goals. Features of the Trio that make it our system of choice include a large patient bore, a wide range of RF coils (including multi-channel array coils) that provide outstanding sensitivity, its speed of image encoding which greatly reduces image susceptibility artifact, excellent gradient linearity enabling a range of imaging protocols unfeasible on other systems, and the ability to perform imaging of the body as well as the brain. An additional Siemens system, will provide other benefits as well including flexibility of scheduling and easy portability of pulse sequences across magnets, familiarity with the programming and user interface, and compatibility with our ongoing instrumentation development efforts. This badly needed shared instrument will enhance the imaging activities of the many PHS supported research programs at the Martinos Center. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application for renewal of the "The Advanced Multimodal Neuroimaging Training Program" seeks continued support for integrated training in neuroimaging through linked Institutional Predoctoral Training and Short-term Research Education components. The goal of the program is to prepare a new cadre of scientists who are focused in the areas of basic and clinical neuroscience and possess the necessary physical science knowledge, computational skills, and familiarity with team science to optimally position them for major contributions using and developing the tools of neuroimaging. Designed to facilitate interdisciplinary interactions in neuroimaging through project-based joint mentorship, the program rests on collaboration between faculty members in the Department of Psychology at Harvard University, the Program in Neuroscience at Harvard Medical School, the Harvard-MIT Division of Health Sciences and Technology, the Department of Brain and Cognitive Sciences at MIT, and the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital. Uniting trainees from diverse backgrounds in a common learning community, this multi-level training program includes predoctoral training as well as a short-term educational program that supports a 2-week Multimodal Imaging Short Course and mentored research training opportunities for individuals at other career stages (e.g., postdoctoral fellows, medical students and residents) who require exposure to and additional education in the technology and application of advanced neuroimaging tools. Through the short course, we are able to extend neuroimaging training beyond the context of traditional graduate-level education. Trainees in the pre-doctoral training program are drawn from Harvard and MIT graduate programs, and carry out research projects jointly supervised by the primary mentor and a co-mentor with complementary expertise. Trainees take additional coursework during the appointment term and attend an AMNTP seminar series and other required programmatic activities. The short-term research education program provides important outreach educational opportunities for scientists at various stages of career development. Central to the research education component is paired mentorship with a senior researcher in the trainee's domain, and opportunities for extended stays to engage in hands-on research experiences. By training these groups to understand the bases of neuroimaging methods and apply them effectively to address the fundamental principles of neuroscience, the ultimate goal of this program is to arm individuals across the career spectrum with the tools and broad-based knowledge of the fundamental neuroscience and the technologies and analytic methods of in vivo neuroimaging to address crucial questions in neuroscience. PUBLIC HEALTH RELEVANCE: This training program builds on the long-established history of excellence in basic and clinical neuroscience training and development of advanced neuroimaging technology within the Boston-area research community. Importantly, however, the program fills a previously unmet need for interdisciplinary neuroimaging research training for individuals from various institutional programs, and with diverse backgrounds, with the goal of educating a new cadre of interdisciplinary basic and clinical neuroimaging scientists.

bioimaging /biomedical imaging; choice

bioimaging /biomedical imaging; choice

bioimaging /biomedical imaging; choice

bioimaging /biomedical imaging; choice

bioimaging /biomedical imaging; choice

[unreadable] DESCRIPTION (provided by applicant): Funding is requested for a dedicated 500 MHz high-resolution, solution and magic angle spinning (MAS) Nuclear Magnetic Resonance (NMR) spectrometer. The proposed instrument will be a crucial component in facilitating the development and synthesis of novel molecular imaging contrast agents and for the identification of biomarkers for specific disease states and biological processes. The NMR spectrometer will serve a large NIH-funded geographically diverse user community encompassing a wide variety of biomedical disciplines. We currently serve users both within the MGH/Harvard/MIT system as well as from around the greater Boston/Cambridge region. However, current users do not have sufficient magnet access, and many others would like to take similar advantage of our facilities, but cannot readily do so. Our current wide-bore 600 MHz MR instrument, which is used for liquids, HR-MAS, and CP-MAS NMR spectroscopy as well as MRI, is overscheduled, operating on a 24x7 basis with reservations needing to be made up to 3 months in advance. The long scan times required for obtaining high resolution MR images and the high demand for scan time make it impossible to use the instrument for regular and routine NMR chemical analysis of contrast agents and biological tissues. The requested equipment would greatly expand our capacity to serve the local NIH- funded user community, as well as offer important analytical chemistry capability to the rapidly expanding user base with molecular imaging interests. In particular, the proposed instrument would allow for "walk-on" scan time for the rapid characterization of intermediates in reaction pathways of novel molecular imaging probes currently being developed and for the identification of biomarkers for different disease states. The institutions to be served include MGH (radiology, neurology, pathology, and surgery), Children's Hospital (orthopaedic surgery), Boston University and Northeastern University. Projects requiring solution NMR spectroscopy include the development and synthesis of (1) dual MRI-histology contrast agents for brain molecular imaging, (2) novel blood-brain barrier permeable contrast agents for brain molecular imaging, (3) amyloid plaque targeting contrast agents for Alzheimer's disease studies, (4) targeted drug delivery vehicles, (5) lymph node specific contrast agents, and the identification of biomarkers associated with (6) stroke and (7) Alzheimer's disease. Projects requiring HR-MAS NMR spectroscopy include identifying biomarkers for (1) breast cancer, (2) inflammatory response in burn tissue (3) HIV injured brain tissue, and (4) ostereoporosis. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Acupuncture, a component of traditional Chinese medicine, has been used for thousands of years to treat a multitude of ailments. Recent scientific evaluation has suggested that this therapy may demonstrate clinical benefit for a number of conditions including chronic pain, though the mechanisms of action have not been well understood. Our well-established group has been a leading force in acupuncture mechanism research for over a decade. In 2003 we were awarded NCCAM's "Center of Excellence for Research on Complementary and Alternative Medicine" (CERC, NCCAM P01 - AT002048, PI: Rosen) for our Center, "The Neurobiological Effect of Acupuncture Action". The focus of our work thus far has been to explore central mechanisms of acupuncture efficacy by evaluating a distributed network of functionally, neurochemically, and neuroanatomically connected brain regions. While our data has consistently demonstrated significant cortical and subcortical effects on brain systems both during and following acupuncture treatment, a fundamental mystery remains - how are signals transduced from the local site of acupuncture stimulation to the brain in order to engender these unique effects? Several groups have pursued the question of peripheral effects of acupuncture treatment, studying both peripheral nerve receptors and connective tissues, but none have connected this work with acupuncture's central action. It is this important scientific gap that our P30 proposal intends to fill. With this P30 Core Center support, we will recruit, hire, and provide laboratory support for junior faculty who will have expertise in evidence-based evaluations of peripheral mechanisms for acupuncture action. By integrating new young investigators into the multidisciplinary team already established as part of our NCCAM Center of Excellence, we will, as a team, now be able to integrate studies of both central and peripheral evaluations of acupuncture effects with multimodal imaging methods, significantly improving our understanding of how and why acupuncture modulates clinically relevant outcome measures. Our established Center of Excellence provides an exceptional mentoring environment for our proposed new investigator. Along with the lead site of the Massachusetts General Hospital, the Osher Research Center at the Harvard Medical School will also be a participating institution, bringing their unique perspective on research into complementary and alternative medical treatments, and providing a rich intellectual community for our new faculty to interact within. PUBLIC HEALTH RELEVANCE: Acupuncture is one of the most well researched and promising therapies within the Integrative Medicine armamentarium. The Martinos Center for Biomedical Imaging has been a leading force in acupuncture mechanism research for over a decade. With this P30 Core Center support, we will expand our focus on central (brain) mechanisms of acupuncture action to include relevant research on mechanisms arising from physiological response at the site of acupuncture stimulation.

DESCRIPTION (provided by applicant): The main goals of the Collaborative Tools Support Network (CTSN) is to 1) provide the collaborative link needed between the BIRN Coordinating Center (BIRN CC) which supplies the BIRN infrastructure and the research community using the tools developed by the current BIRN testbeds and 2) provide outreach to scientific communities (including domains other than neuroimaging) and to provide those communities with assistance in adopting the BIRN resources. The CTSN brings together the Principal investigators, Project Managers and key personnel of each of the BIRN testbeds go off-line. This model will allow the testbed institutional memory and knowledge base to remain intact and be available to the larger community, while allowing the resources to be used in flexible manner as new collaborative projects emerge in fields no covered by the currents testbeds. Our experience has shown that groups seeking BIRN technology and assistance require broad range of time investment on the part of the CTSN. Therefore, we have chosen a model that responds to these needs. The CTSN will provide expert assistant for projects ranging from short term (e.g., help with tool Installation) to the long term (e.g., CTSC's that seek integrate BIRN technology into their existing environment). In addition, the CTSN will provide vigorous outreach to the scientific community. NIH rules now require data sharing plans for grants with costs over $500,000. The CTSN will help BIRN position itself as a data-sharing resource for the NIH community. CTSN members have deep experience In the many steps to data sharing, from writing data-sharing applications to local Institutional Review Boards, to the modification of database schemas as data from new domains are added, to the deidentificatlon of data. The deep experience that CTSN members also have in developing tools to interoperate with the BIRN infrastructure will also be crucial as members of the outside community bring their tools into the BIRN toolset.

DESCRIPTION (provided by applicant): We seek support to recruit an extremely promising young radiochemist to join a substantial group of neuroscience investigators. Our candidate would be a new faculty member, does not have a current tenure-track appointment, has outstanding research training in relevant areas, and would be enabled through these funds to develop a strong independent line of research in novel methods of neuroscience PET probe development, with particular relevance to substance abuse. The candidate would be able to have joint appointments at Massachusetts General Hospital, Harvard Medical School, and the Massachusetts Institute of Technology, enabling the candidate to access a wide variety of research resources ranging from clinicians to imaging scientists to medicinal and synthetic chemists. This P30 award would enable us to offer the candidate the type of substantial startup package needed to attract such a candidate: chromatographs, mass spectrometers, and other equipment that a new faculty member needs. This new recruit would substantially complement and expand the breadth of the existing faculty in and around the Martinos Center for Biomedical Imaging and would greatly facilitate NIDA-funded research. PUBLIC HEALTH RELEVANCE: This application seeks support for a promising new faculty member that would develop new approaches for creating molecular imaging agents. These agents have the potential to provide personalized medical approaches as well as give insight into how many diseases occur, how treatments work, and how treatments fail. This work has broad public health significance for understanding drug abuse.

This proposal aims to support the development of a new Connectom diffusion imaging system, designed with advanced gradient technology (300 mT/m gradient set in an advanced 3T instrument), and optimized for the collection of in vivo structural connectivity data from healthy adult humans. Following installation and optimization of this novel system, we will scan normal human subjects, including a number of subjects recruited from the other HCP site, and begin initial development of software to analyze this data and compare, document and disseminate the results obtained against those developed by other connectomics efforts, including the other HCP site. This work will be integral part of the collaborative HCP effort to construct a map of the human connectome that represents the structural and functional connections in vivo within a brain and across individuals. As a result, this work has significant potential to dramatically advance capabilities to measure the human Connectome, by aggressively optimizing non-invasive imaging technology toward Connectome measurements. This effort builds upon existing multidisciplinary collaboration between Massachusetts General Hospital/Harvard Medical School (MGH) and the University of California-Los Angeles (UCLA), and employs a multiple PI leadership approach, providing a rigorous system of leadership, organization, and oversight to this program of bioengineering, optimization and validation that aims to improve the ability of Diffusion Spectrum Imaging (DSI) to map connectivity in the living human brain.

DESCRIPTION (provided by applicant): While acupuncture has been shown to be effective for chronic low back pain (cLBP) in many clinical trials, there is a current state of uncertainty as to why acupuncture is effective. In multiple trials, acupuncture does not demonstrate significant improvement over placebo controls based on sham needling, which can involve insertive or non-insertive needling with a device that presses against the skin. However, the use of sham needling as placebo control has been criticized since it may be an active therapy akin to acupressure. Ultimately, this state of uncertainty arising from acupuncture clinical trials exists because we lack understanding about the mechanisms of action underlying real versus various forms of sham acupuncture. Specifically, we do not know just how important needle insertion and somatosensory afference are to the mechanisms underlying acupuncture analgesia in cLBP. There is reason to believe that real acupuncture may have different mechanisms from sham acupuncture, and we propose that neuroimaging can inform a testable neurobiological model that identifies diverse mechanisms of action for acupuncture therapy with versus without somatosensory afference. These hypotheses will be tested on a specific chronic pain population, idiopathic cLBP, which has a significant central pain component characterized by aberrant somatotopy and augmented brain response to experimental pain (hyperalgesia). The brain correlates of clinical pain in cLBP have been less well characterized, but our own data suggests that clinical pain is associated with increased intrinsic functional connectivity between pain processing brain regions (e.g insula) and specific intrinsic connectivity networks. These networks include the executive attention network (EAN) and default mode network (DMN), a network thought to underlie self-referential cognition and modulated by acupuncture. We propose that real and different forms of sham acupuncture differentially modulate these networks, and alter somatotopy. Our overall goal is to evaluate whether the brain neurocircuitry subserving cLBP responds differentially to real versus sham acupuncture with and without somatosensory afference. To test our specific hypotheses, we will employ functional magnetic resonance imaging (fMRI) to assess brain networks subserving both clinical and experimental pain, acupuncture stimulation, and somatotopy in cLBP patients. These measures will be performed at baseline and following 7 weeks of (a.) acupuncture, ACUP; (b.) sham acupuncture with somatosensation, SHAM-sn; (c.) sham acupuncture without somatosensation, SHAM-ml\ or (d.) wait list, WL. Aim 1 will characterize the pain neurocircuitry in cLBP, as well as low back SI somatotopy, and brain response to acupuncture stimuli. Aim 2 will evaluate longitudinal effects of ACUP vs. SHAM-sn on brain networks and SI somatotopy in cLBP, while Aim 3 will evaluate the longitudinal effects of SHAM-sn vs. SHAM-ml on these same neuroimaging markers. Understanding the neural influence of somatosensation on acupuncture placebo effects will significantly impact our understanding of acupuncture and allow for development of more inert acupuncture placebos.

DESCRIPTION (provided by applicant): Assessment of anti-angiogenic therapies for the most severe form of brain cancer, glioblastoma, is extremely timely given the recent approval of bevacizumab yet the moderate response rate and the challenging side effects of these therapies. Clinical decision-making tools are badly needed;fortunately, our recently published data suggest that measurement of microvascular properties of the tumor using MRI and gadolinium-based approaches could be very useful, as with proper quantitation these methods appear to be capable of serving as an effective prognostic imaging biomarker, and may be beneficially combined with blood biomarkers. We propose to join the NCI's Quantitative Imaging Network (QIN) and develop improved analysis methods for dynamic contrast enhanced MRI and dynamic susceptibility MRI that will improve quantification and decrease variability. We propose to develop techniques that will be applicable in the multicenter setting through a bottom-up approach of simulations, phantom studies, retrospective analysis, and prospective analysis in patients undergoing treatment with anti-angiogenic therapies. We anticipate that our proposed approach, in particular through working in close harmony with the QIN, will improve the reliability of advanced microvascular MRI methods as potential imaging biomarkers, and pave the way for a clinically useful decision-making tool. RELEVANCE (See instructions): Advanced MRI methods may improve our ability to provide an accurate prognosis and potentially guide treatment choices for glioblastoma patients. Our proposed research will help establish a common, standardized approach to acquisition and analysis of two forms of vascular MRI that have shown excellent promise. We will do this by careful reduction of variability and by close participation in the National Cancer Institute's Quantitative Imaging Network. These efforts will enable these advanced techniques to become more widely available and more appropriately establish their benefit to patients.

The Neuroimaging and Biostatistics (NIBS) Core, under the leadership of Dr. Bruce Rosen, will provide technical support to synthesize and integrate neuroimaging and statistical methods and analyses across the CERC Projects. Dr. Rosen, who is also the PI ofthe proposed CERC to investigate the central mechanisms of acupuncture action in chronic low back pain, is Director of the Athinoua A. Martinos Center for Biomedical Imaging at MGH. The Martinos Center has provided the broad research community with a range of innovations in the domains of MRI acquisition and analysis, many of which our group has extensive experience using to study acupuncture mechanisms in the brain. The three Projects in our proposed CERC focus on evaluating how different components of acupuncture therapy contribute to analgesia in chronic low back pain (cLBP). By providing a common image acquisition and analysis framework, the NIBS Core will facilitate the ability to perform intra- and inter-project analyses as well as larger-scale analyses that integrate not only across the CERC, but also across our other related NCCAM-funded studies, allowing us to address larger-scale questions about the neurobiology of acupuncture action in chronic pain conditions, and thus increase the value of such data to the broader community when shared according to our Data Sharing Plan. Specifically, the NIBS Core will seek to optimize and integrate neuroimaging methods across projects, which will be critical for cross-project synergy and pooled analysis. Further, the Core aims to provide unified, comprehensive data analysis and biostatistical support for all projects, as well as neuroanatomical support to ensure that our hypotheses and inferences gleaned from the neuroimaging data are firmly grounded in a consistent and up-to-date neuroanatomical framework. The NIBS core will also aim to organize a unified database and data sharing infrastructure for data collected across projects. Finally, this core will support and/or perform exploratory analyses on combined datasets collected from all three projects.

A growing body of evidence substantiates that acupuncture treatment significantly improves clinical outcomes for patients with chronic pain disorders, and specifically for patients with chronic Low Back Pain (cLBP). Major stakeholders recommend acupuncture as one possible treatment option, despite the fact that in most cases, especially in large trials, sham (placebo) treatment is equally efficacious to real acupuncture, because both treatments are superior to optimal mainstream care or no-treatment. To more fully understand acupuncture treatment and how to best incorporate it into clinical practice, understanding placebo effects is urgent. Further, extensive research from our own group suggests that sham acupuncture has enhanced placebo effects compared to placebos for conventional treatments (e.g. pills or creams). Mechanistic work using a conditioning expectancy manipulation in healthy subjects to investigate the neural basis for analgesia after treatment with real acupuncture or placebo acupuncture suggests that this difference is not because of differential expectations. A critical question is, do different routes of administration configure unique neural mechanisms of placebo analgesia? Published fMRI data from our team demonstrates distinctly different mechanisms for real and placebo acupuncture, despite comparable levels of pain relief. Comparing our fMRI data with published studies from other laboratories suggests different mechanisms between sham acupuncture and placebo creams. Importantly, levels of expectation of pain relief were experimentally enhanced by the same conditioning mechanism. Notably, very little work has been done to investigate the neural mechanism underlying placebo effects in chronic pain patients. In this study, we will directly compare cohorts of cLBP patients and matched healthy control subjects to investigate the impact that living with significant, chronic pain has on the neural mechanisms underlying the expectation component of analgesic response to real acupuncture and placebo acupuncture. This study will expand our understanding of acupuncture's potential role in the management of cLBP and clarify the nature of placebo responses.

Recent large randomized controlled trials (RCTs) for cLBP indicate that acupuncture is superior to both optimal guideline-based mainstream care and waitlist controls. Yet, the medical community's acceptance of acupuncture as a treatment option has been hampered by a failure to find significant clinical differences between verum and sham (placebo) acupuncture. Importantly, despite their similar clinical effect, studies from both our and other groups found that real and sham acupuncture treatments work through different brain mechanisms to produce treatment effect. In parallel, previous studies have demonstrated that context (i.e., the broad non-specific effects of treatment ncluding patient-practitioner relationship, expectation, warmth, support, attention, and elaborate ritual) can have significant and meaningful impact on many disorders. Recent RCT trials by our group using acupuncture as the method of treatment also demonstrated that, relative to treatment delivered with a limited provider engagement, treatment delivered with augmented context effect produces a significant increase in clinical benefit. The relative ease by which acupuncture efficacy can be systematically varied by context makes acupuncture an ideal choice for future context experiments. Notably, neural longitudinal mechanisms underlying the two context conditions (limited versus augmented) have yet to be studied. We propose to conduct a novel mechanistic longitudinal 2x2 factorial study on cLBP patients using the cutting edge neuroimaging technique of arterial spin labeling (ASL) and BOLD fMRI. Eighty patients with cLBP will be randomized to one of five arms: A) augmented context placebo (sham acupuncture); B) limited context placebo (sham acupuncture); C) augmented context verum acupuncture D) limited context verum acupuncture. The endpoints will include both clinical cLBP outcomes and neuroimaging biomarkers. We believe that this study will elucidate the mechanisms underlying both context effect and acupuncture, potentially translating to maximization of clinical treatment benefits for cLBP and/or use of alternative treatments.

DESCRIPTION (provided by applicant): This resubmission application requests funding to support the purchase of a 3 Tesla Siemens MAGNETOM Skyra MRI system at the Athinoula A. Martinos Center for Biomedical Imaging. The proposed instrument, which will upgrade the Martinos Center's existing 11-year-old 1.5 Tesla Siemens Avanto scanner, will be dedicated for whole-body human MRI research and will support the funded research of a large and growing community of clinical/translational investigators at the Massachusetts General Hospital and neighboring institutions. The need for the proposed 3T MRI system has a number of facets. First, the existing 1.5T scanner no longer provides the technological edge to drive our investigators' research to the next level. Higher field strength provides better image quality, and greater sensitivity to the subtle differences in brain structure or function that may characterize significant physiological and pathological differences. In recognition of the benefits of scanning at 3T versus 1.5T, the clinical/translational investigators within our community have increasingly transition their studies to 3T. However, as their numbers and their research grow, the Center's ability to accommodate demand is also increasingly challenged. Although the Martinos Center has the great fortunate of having several research-dedicated 3T MRI systems already on site, each has a specific defined research mission that includes development of high-N RF array coils and gradient technologies (Bays 3 and 4, respectively). Because the ongoing technology development work means these systems often undergo hardware modifications, they do not offer the stability needed to support longitudinal clinical research. As a result, broadly, clinical and translational research studies are hindered by a variety of factors that include a shortage of available scan time, instability for longitudinal clinical studies. The proposed instrument will not only enhance the ability of clinical/translational investigators to conduct their current research, it will also provide opportunities for fruitful new projects and collaborations. With the patient-friendly imaging environment of the proposed instrument brought to bear on these projects, we anticipate that the broad and active growing community of clinical/translational scientists engaged in MRI-based studies of major human disorders will be poised to find exciting new diagnostic and therapeutic applications relevant to a many neurological and psychiatric diseases. PUBLIC HEALTH RELEVANCE: Imaging technologies such as MRI have enabled clinical investigations to better characterize human disease and, thus, inform the development of more improved treatment. Newer-generation technologies designed for patient-friendly operation offer dramatic improvements in image quality to better detect the physiological subtleties that may differentiate health from disease, and in turn advance understanding of human disease to optimize patient care. We purpose to upgrade our aging clinically oriented MRI scanner in order to leverage critical cutting-edge advances in MRI technology to support ongoing and developing areas of clinical research at the Massachusetts General Hospital.

Core C The Clinical Core (CC) of the CERC, under the joint direction of Drs. Ajay Wasan and Ted Kaptchuk, will facilitate all clinical activities of the three proposed Projects, providing supervisory support and critical expertise to unify all clinical aspects of our human subjects experimental designs. The success of the entire CERC endeavor depends to a great degree on the recruitment, characterization, and retention of patients. The investigators have extensive, published experience recruiting patients for large acupuncture trials, and we anticipate that these methods will yield the target enrollment. Dr. Wasan, pain specialist, psychiatrist and clinical researcher who is expert in the area of low back pain, will leading the screening and characterization of all patients recruited for all CERC projects. Important to the overall CERC research design, treatment context is unique in each Project: equipoise in Project 1, augmented vs. limited in Project 2, and fidelity to treatment protocols in Project 3; adherence to the characteristics of each context is critical. The CC has unique experience establishing replicable treatment contexts in acupuncture trials, and will ensure compliance to context in all Projects. Quantitative sensory testing (QST) will be used in Projects 1 and 2 to assess potential abnormalities of mechanisms underpinning pain perception, interpersonal differences in pain responses, and intrapersonal changes in pain processing as a function of treatment or intervention. Because potential emergencies and medical and psychiatric complications may occur in all of the CERC projects, it is important that these studies be conducted with the highest degree of patient safety; Dr. Wasan will provide critical expertise in and oversee these procedures. In brief, to ensure the successful completion of the Projects the CC will: 1) recruit, characterize, randomize, and support retention of subjects; 2) ensure fidelity to acupuncture protocols and context procedures for all Projects; 3) implement the no-treatment waitlist control for Projects 1 and 2; 4) supervise, perform, and analyze quantitative sensory testing for Projects 1 and 2; 5) provide back-up medical care for emergencies, medical or psychiatric complications related to acupuncture treatment for all Projects; and 6) organize and interact with Data Safety Monitoring Board for all Projects.

Core A The Administrative Core, designed to ensure coordinated operation of all CERC Projects and Cores, will provide administrative leadership and resources and infrastructure across all Projects and Cores to enable efficiency and integration of the overall CERC. The Core will support unified design and execution of all projects, to facilitate the overall scientific aims of this research, and put in place a framework for future NCCAM research endeavors that may develop from the research of the CERC. In this way, the Administrative Core will play a critical role in strengthening and extending the overall CERC research effort. The Core Director will be responsible for oversight of all administrative activities and provide overall guidance and advisory support to the Project and Core Leaders and co-investigators. The Scientific Director will work closely with the Core Director to chart the scientific goals and vision for the CERC and facilitate inter-project cohesion and collaboration. He will act as a liaison between the Project Leaders and with the External Advisory Committee members; he will also manage CERC outreach activities. A Program Manager and Project Administrator will perform day-to-day administrative operations in a facilitative manner, so as to free the investigators to focus on scientific matters. An Internal Management Committee will meet monthly to all CERC activities, including management, utilization, personnel and Core performance, quality control, budgetary and policy matters. An External Advisory Committee made up of individuals with expertise in a broad range of fields relevant to acupuncture and chronic low back pain research will meet annually to review research progress and provide guidance and stragtegic direction for the overall functioning of the CERC. The Administrative Core will specifically provide clerical and recordkeeping duties, monitor budgets and spending, purchase and maintain supplies and vendor contacts, organize meeting logistics and travel arrangements, coordinate the preparation of progress reports, and support CERC dissemination by assisting with manuscript and presentation preparation as well as maintaining the CERC website.

While acupuncture has been shown to be effective for chronic low back pain (cLBP) in many clinical trials, there is a current state of uncertainty as to why acupuncture is effective. In multiple trials, acupuncture does not demonstrate significant improvement over placebo controls based on sham needling, which can involve insertive or non-insertive needling with a device that presses against the skin. However, the use of sham needling as placebo control has been criticized since it may be an active therapy akin to acupressure. Ultimately, this state of uncertainty arising from acupuncture clinical trials exists because we lack understanding about the mechanisms of action underlying real versus various forms of sham acupuncture. Specifically, we do not know just how important needle insertion and somatosensory afference are to the mechanisms underlying acupuncture analgesia in cLBP. There is reason to believe that real acupuncture may have different mechanisms from sham acupuncture, and we propose that neuroimaging can inform a testable neurobiological model that identifies diverse mechanisms of action for acupuncture therapy with versus without somatosensory afference. These hypotheses will be tested on a specific chronic pain population, idiopathic cLBP, which has a significant central pain component characterized by aberrant somatotopy and augmented brain response to experimental pain (hyperalgesia). The brain correlates of clinical pain in cLBP have been less well characterized, but our own data suggests that clinical pain is associated with increased intrinsic functional connectivity between pain processing brain regions (e.g insula) and specific intrinsic connectivity networks. These networks include the executive attention network (EAN) and default mode network (DMN), a network thought to underlie self-referential cognition and modulated by acupuncture. We propose that real and different forms of sham acupuncture differentially modulate these networks, and alter somatotopy. Our overall goal is to evaluate whether the brain neurocircuitry subserving cLBP responds differentially to real versus sham acupuncture with and without somatosensory afference. To test our specific hypotheses, we will employ functional magnetic resonance imaging (fMRI) to assess brain networks subserving both clinical and experimental pain, acupuncture stimulation, and somatotopy in cLBP patients. These measures will be performed at baseline and following 7 weeks of (a.) acupuncture, ACUP; (b.) sham acupuncture with somatosensation, SHAM-sn; (c.) sham acupuncture without somatosensation, SHAM-ml\ or (d.) wait list, WL. Aim 1 will characterize the pain neurocircuitry in cLBP, as well as low back SI somatotopy, and brain response to acupuncture stimuli. Aim 2 will evaluate longitudinal effects of ACUP vs. SHAM-sn on brain networks and SI somatotopy in cLBP, while Aim 3 will evaluate the longitudinal effects of SHAM-sn vs. SHAM-ml on these same neuroimaging markers. Understanding the neural influence of somatosensation on acupuncture placebo effects will significantly impact our understanding of acupuncture and allow for development of more inert acupuncture placebos.

DESCRIPTION (provided by applicant): Biologists and other human-health related scientists have been employing informatics approaches that integrate disparate data types (e.g. molecular, clinical) to make new discoveries about the biological basis of diseases, the treatment of diseases, and response to therapy. Human imaging is a rich source of phenotypic information that could be integrated with these other data, but they have been largely inaccessible to biologists for use in their investigations because the information contained within them is usually not quantitative. Making images and quantitative characterizations of visualized tissues available to the larger community holds great promise to accelerate research and discovery including the development of imaging biomarkers in cancer. The first critical step in the development and use of imaging biomarkers in cancer is the segmentation of the target lesions from their environments. Once the lesions have been segmented, one can computationally characterize many lesion image features for integration with other data types. To accelerate progress towards developing and optimizing algorithms for lesion segmentation and characterization, we will develop, deploy, and disseminate an informatics platform. The Cloud-based Image Biomarker Optimization Platform (C-BIBOP) will include 1) imaging data stored locally or accessed through curated repositories such as the Cancer Imaging Archive, 2) a set of segmentation and feature computation algorithms that can be run on these or newly uploaded data, 3) the outputs of lesion segmentation algorithms for these data, 4) the outputs of feature computation algorithms for these data, and 5) a set of metrics and visualization tools for the comparison of the performance of these algorithms, segmentations and features. Specifically, we will develop the C-BIBOP for the large-scale central analysis of multi-institutional quantitative image data by developing a cloud-based infrastructure to support customized computing environments, experiments that include images and associated meta-data, and a reporting module that performs comparisons, statistical analyses and visualizations of the results of segmentation and characterization. The basic infrastructure will be initially be populated with baseline algorithms, segmentations and image descriptors developed by Columbia, MGH, Moffitt, and Stanford (CMMS) investigators as well as limited datasets. We will deploy the C-BIBOP on a cloud platform, develop and share experiments consisting of data, algorithms and exploration of parameter spaces, and evaluate it at the participating institutions with state-of-the-art algorithms and well-curated datasets. Finally, we have identified a set of early adopters and beta-testers from within the Quantitative Imaging Network, and external collaborators and industrial partners who have indicated their willingness to contribute algorithms, data and results to C- BIBOP. We will host at least two permanent online collections of images and maintain the best segmentations and characterizations available that can be utilized by participants at anytime.

? DESCRIPTION (provided by applicant): NRM 2016 Meeting Abstract The International Symposium on Functional Neuroreceptor Mapping of the Living Brain is a biennial meeting of researchers and physicians in academia and the pharmaceutical industry whose research focuses on the development of noninvasive imaging techniques-including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) and other molecular imaging methods-to functionally characterize and quantify neurotransmitters (e.g., serotonin-2A, dopamine-D2) and other neurobiological processes (e.g., amyloid, neuroinflammation) in the living brain. The overarching goals of scientific sessions of the meeting are to apply noninvasive neuroimaging methods to: 1) improve the understanding of the pathophysiology of neurodegenerative diseases and psychiatric disorders, addictive disorders, and aging and psychological processes; 2) develop improved methods of quantifying neuroreceptor function in vivo; 3) effectively use molecular imaging techniques to accelerate the process of central nervous system (CNS) drug development; 4) expand molecular imaging measures to new areas such as imaging psychological processes (e.g., cognition, stress); and 5) develop methods and applications of multimodality imaging (e.g., PET/fMRI). The scientific program for the meeting will focus on basic and clinical research that is of direct relevance to NIH Neuroscience sponsored research. The main component of the symposium program will include both platform and poster presentations. Session topics may include: neuroinformation; dopamine receptor dynamics and function; multi-receptor circuitry underpinning reward circuitry; neuroinflammation; applications of neuroreceptor mapping to clinical trials and drug development; advanced modeling of receptor dynamic and trafficking; novel approaches for neuroreceptor mapping, including multimodal approaches; proteopathy; PET-MR roundtable; novel radiotracer development; and translation applications of neuroreceptor mapping. The program will also include two special lectures and networking events. This symposium will leverage the breadth of expertise of a truly international and multidisciplinary group of researchers and physicians, who work in the area of functional neuroimaging and related fields, to identify and explore translational research opportunities that may advance clinical diagnostics and drug development and to establish and foster communication, collaboration, and fellowship among the group.

The Administrative Core is designed to ensure successful operation of our proposed Center of Excellence for Research on Complementary and Integrative Health (CERCIH), leading to success in achieving the overall research goals of all 3 Projects. This success depends heavily on coordinated functioning of all Projects and Cores and our Core will provide administrative leadership, resources and infrastructure to support not just the three Projects, but also the Neuroimaging and Biostatistics (NIBS) Core B, and Clinical Core C. By liaising between projects, the Administrative Core will play a role in supporting the unified design and execution of all Projects and put in place a framework for future CERCIH research directions. In this way, the Administrative Core will play a critical role in strengthening and extending the overall CERCIH research effort, allowing the Project and Core Leaders and their teams to maintain focus on Project-specific as well as CERCIH-wide scientific goals. The Aims of the Administrative Core will be to provide administrative leadership and structure to integrate, synergize, and coordinate the research activities of each of the CERCIH Projects and facilitate the overall performance of CERCIH research. We will also foster constructive and dynamic interactions and communications among the CERCIH investigators, as well as with the broader scientific community. The Core will also be responsive to the requirements and regulations of the NIH, NCCIH, and the sponsoring institution. Finally, we will provide services to support the dissemination of the research results generated by the CERCIH to the larger research community.

DESCRIPTION (provided by applicant): This P41 Biotechnology Resource Grant application seeks renewed support for our successful efforts to develop and apply innovative neuroimaging technologies within the highly integrated multimodal framework of the Center for Functional Neuroimaging Technologies (CFNT). The overall goal of this established NIBIB Biomedical Technology Resource Center (BTRC) is to provide advanced technology resources to more closely examine, and thus better understand, the human brain in health and disease. To this end, we seek to develop new techniques and advance existing technologies to acquire and analyze functional images of the working brain, with unprecedented physiological precision and spatiotemporal resolution, and to deploy these innovative tools to promote investigation of complex neuroscientific questions. Through coordinated research and development, collaborative research, service use, training and dissemination activities, our BTRC has built a standard of excellence in developing, sharing, and supporting the use of multimodal imaging tools that have consistently advanced capabilities for research that spans many basic science and clinical domains. Central to this effort are our four Technology Research and Development (TRD) projects to improve and extend techniques for non-invasive magnetic resonance image analysis (Project 1) and acquisition (Project 2), electromagnetic source imaging (Project 3), and optical neuroimaging (Project 4). Directly motivating the Aims of these TRD projects is a strong network of Collaborative Projects, which both challenge the TRDs to continue to innovate the next-generation neuroimaging tools, and reciprocally, employ the new tools we develop to drive their own research forward in new directions. Another essential element in this framework is the extensive application of our resources by a wide and diverse Service Users community. Finally, the TRDs, Collaborative and Service Projects contribute to the BTRC's Training and Dissemination mission, which additionally includes multiple dedicated Fellowships and Workshops, strong web presense, and important industrial partnerships, providing multiple channels to share the knowledge needed to apply the tools we develop with the scientific community locally, nationally, and internationally.

Abstract While many mind-body therapies have shown promise for chronic pain, the efficacy of any single-modality treatment is typically modest, and finding a way to boost clinical outcomes is a crucially important goal. It is well documented, and recommended in the recent Institute of Medicine (IOM) report on pain, that a multimodal approach is optimal for pain management. Multimodal analgesic strategies are thought to enhance benefits to patients by simultaneously targeting multiple pathways that contribute to chronic pain. Mind-body therapies have shown promise for pain, and many such therapies (e.g., mindfulness meditation (MM) training) are actually characterized as predominantly ?mind,? taking advantage of top-down brain-based mechanisms of action, without fully integrating bottom-up ?body?-based mechanisms. A greater use of ?mind? and ?body? elements via a multimodal therapeutic approach may enhance clinical outcomes through neurophysiological integration within the central nervous system (i.e., brain). Our overall goal in this proposal is to evaluate how and where such integration takes place for a common chronic pain disorder - migraine. Our 3 Projects will target 3 critical and inter-related pathophysiological processes that characterize migraine headache, and how both ?top-down? and ?bottom-up? interventions mitigate this pathology. To augment MM training, we propose a specifically-targeted, bottom-up therapy that has also shown promise for migraine - transcutaneous vagus nerve stimulation (tVNS). We will use a recently developed optimized tVNS approach that gates stimulation to the respiratory rhythm (i.e., respiratory-gated auricular vagal afferent nerve stimulation, RAVANS), which enhances the potential synergy, both conceptually and neurophysiologically, of combining tVNS with MM, with its own focus of non-judgmental attention on breathing with a calm and alert mind. All three projects will apply neuroimaging and other physiological and behavioral tools at baseline and following 8-weeks of a combination of RAVANS or Sham tVNS with MM or education control. Aim 1, addressed by Project 1, will investigate brainstem and cortical mechanisms for reducing cortical/subcortical hyperexcitability. Aim 2, addressed by Project 2, will evaluate MM+RAVANS tVNS improvements in autonomic and central autonomic network dysfunction. Aim 3, addressed by Project 3, will use multimodal PET/MR imaging and a recently developed ligand for glial activation to assess anti-neuroinflammatory effects of MM+RAVANS tVNS therapy. Aim 4 will investigate how the neurobiological changes assessed in Aims 1 to 3 are inter-related through mediation and other analyses performed by the Neuroimaging and Biostatistical Core, while the Clinical Core and Administrative Core will support recruitment and administration of our synergistic study design.

The  Clinical  Core  (CC)  of  the  Center  of  Excellence  for  Research  on  Complementary  and  Integrative  Health  (CERCIH)  will  facilitate  the  clinical  activities  of  the  three  proposed  Projects,  providing  support  and  expertise  to  unify  all  clinical  aspects  of  our  human  subjects  experimental  designs.    The  CC  will  recruit,  screen,  characterize,  and  enroll  120  subjects  with  recurrent  migraine  headaches  and  30  age-­  and gender-­matched healthy controls.  Mostly using physician referrals and our Research Patient Data  Registry (RPDR), the core will utilize a highly skilled and experienced team to supervise and implement  these  goals.  The  CC  will  be  the  central  randomization  point  for  Projects  1,  2,  and  3  and  provide  the  network  and  referrals  to  support  recruitment  of  all  subjects  and  ensure  adherence  to  the  common  inclusion/exclusion  criteria  utilized  for  all  three  Projects.  The  CC  will  randomize  subjects  using  a  2  x  2  design:  Mindfulness-­Based  Stress  Reduction  (MBSR)  versus  Health  Education  Training  (HET)  X  transcutaneous vagus nerve stimulation (tVNS) compared to sham tVNS.  The CC will ensure that the  MBSR and HET are delivered correctly and adhere to protocol. The CC will recruit, train and supervise  the  MBSR  group  leaders  who  will  perform  all  of  the  necessary  trainings  and  education  sessions.  The  CC  will  refine  and  implement  the  methodologies,  including  audiotaping  and  fidelity  rating  of  training  sessions,  to  ensure  group  leader  protocol  compliance.  The  CC  will  use  accelerometer-­based,  ecologic  momentary  assessment  to  measure  mindfulness  practice  dose  during  the  study  so  as  to  ensure  accurate  measurement  of  individual  subjects?  level  of  mindfulness  practice.    The  CC  will  oversee  and  integrate  our  respiratory-­gated  tVNS  approach  with  MBSR  and  HET  sessions,  including  the  sham  tVNS,  where  needed.  The  CC  will  ensure  that  devices  will  be  available  to  accommodate  all  subjects  and  that  the  units  are  reliably  utilized  within  each  session.    In  collaboration  with  the  biostatistics  core,  the  CC  will  collect  self-­report  measures  to  investigate  relevant  clinical  correlates  such  as  headache  frequency and intensity, days of lost function, perceived stress, and pain interference. The CC will also  collect  self-­report  data  for  mediation  and  moderation  analyses,  including  chronic  disease  self-­efficacy,  perceived  control,  anxiety,  depression,  trait  mindfulness,  mindfulness  practice  behaviors,  self-­ compassion,  interoceptive  awareness,  and  emotional  dysregulation.    While  infrequent,  the  CC  will  be  available  to  provide  medical  coverage  and  assessment  for  any  medical  or  psychiatric  adverse  effect  from tVNS and/or mindfulness.  The CC will meet once per year with the Data Safety Monitoring Board  to  review  and  discuss  any  new  internal  or  pertinent  external  data,  as  well  as  to  monitor  safety,  effectiveness,  and  study  conduct.    The  CC  will  also  coordinate  any  necessary  independent  monitoring  activities as required, and successfully manage one common IRB across the 3 projects. 

SUMMARY We present Connectome 2.0, the next-generation human MRI scanner for imaging structural anatomy and connectivity spanning the microscopic, mesoscopic and macroscopic scales. This work builds upon our expertise in engineering the first human Connectome MRI scanner with 300 mT/m maximum gradient strength (Gmax), the highest ever achieved for a human system, for the Human Connectome Project (HCP). The goal of the HCP was to map the macroscopic structural connections of the in vivo healthy adult human brain using diffusion tractography. While this instrument has made important contributions to our understanding of macroscale connectional topology, our experience with the scanner over the last seven years has taught us that dedicated high-gradient performance scanners can also acquire a rich array of diffusion measurements that provide unparalleled in vivo assessment of neural tissue microstructure, such as the relative size and packing density of cells and axons. However, the current Connectome instrument is limited in its ability to resolve the full range of length scales needed to probe the microscopic and mesoscopic structure of the brain, due to basic design limitations, important technical elements, and biological interactions with the large rapidly switching gradients. Our experience with the first generation Connectome scanner and realization of its limitations motivates our multi-site proposal for the next generation human Connectome MRI scanner (Connectome 2.0) to achieve sensitivity to a broader range of cellular and axonal size scales, morphologies, and interconnections represented throughout the brain. Our goal here is to translate our initial experience into building a one-of-a-kind high-slew rate, ultra- high-gradient strength MRI scanner that is optimized for the study of neural tissue microstructure and neural circuits across multiple length scales. In order to maximize the resolution of this in vivo microscope for studies of the living human brain, we will push the diffusion resolution limit to unprecedented levels by (1) nearly doubling the current Gmax to 500 mT/m and tripling the maximum slew rate to 600 T/m/s; (2) pushing the limits of the RF receive coils and gradient characterization to enable maximum sensitivity with greatly reduced artifacts using real-time eddy current corrected dMRI acquisitions; (3) developing new pulse sequences to achieve the highest diffusion- and spatial-resolution ever achieved in vivo; and (4) calibrating the measurements obtained from this next generation instrument through systematic validation of the diffusion microstructural metrics in high-fidelity phantoms and ex vivo brain tissue at progressively finer scales. We envision creating the ultimate diffusion MRI machine capable of addressing the BRAIN 2025 mandate to image across scales, from the microscopic scale needed to probe cellular heterogeneity and plasticity, to the mesoscopic scale for enumerating the distinctions in cortical structure and connectivity that define cyto- and myeloarchitechtonic boundaries, to improvements in estimates of macroscopic connectivity.

ABSTRACT The goal of this proposal is to purchase a Bruker AV-Neo console to replace the out-of-date Siemens console of the 14T horizontal MR scanner (13cm bore), which has been dedicated to supporting the high-resolution anatomical and functional dynamic brain mapping of animals and ex-vivo imaging. The Martinos Center at the Massachusetts General Hospital has been at the forefront of developing advanced functional mapping methods, e.g., functional MRI, and implementing the cutting-edge MRI methods to bridge the basic and translational studies. To pursue the next-generation cutting-edge imaging methodology and prepare for the higher field MRI translational studies, there is an urgent need to improve our 14T MRI preclinical platform for high-resolution animal and ex vivo imaging. In particular, the proposed 14T MR console upgrade will boost the translational potentials of the eight NIMH-funded projects with a synergistic goal to bridge cellular and microvascular anatomy and functional dynamics from animal to human brains. In addition, this proposal will support nine mental-health- related projects funded by other NIH Institutes, presenting critical translational efforts on the mechanistic studies of brain disorders including Alzheimer?s Diseases (AD), cerebrovascular dementia, migraine, brain tumor, traumatic brain injury, and cardiac arrest (AC)-induced coma. The highly synergistic and collaborative brain research projects outlined in our proposal can be summarized in three main themes related to mental health: 1) Neurovascular dynamic signaling, 2) Cutting-edge neuroimaging methodology, 3) Multimodal mechanistic signatures of brain disorders and injury models. We have established the 14T-based multi-modal neuroimaging platform to combine the high-resolution anatomical and functional MRI imaging with the emerging neuro- techniques, e.g. optogenetics, optical fiber-mediated biosensor recording of Calcium, Glutamate, etc, promoting novel mechanistic understanding of the complexity of brain function. The Bruker AV-Neo system will provide key technological innovations to improve the performance of the novel brain mapping methods, e.g. the single-vessel fMRI, line-scanning fMRI, RF slab-specific diffusion-weighted MRI, given the state-of-the-art electronics and software design. Therefore, the proposed instrument upgrade would not only accelerate the progress of the listed projects but also facilitate the translation of cutting-edge MR methodologies as a truly multidisciplinary, regional resource for PHS funded investigators.

Overview of the Proposed Resource ? Abstract The goal of the Center for Mesoscale Mapping is to drive the convergence of microscopic- and macroscopic- scale evaluation of brain structure and function for human translational neuroscience, by developing and applying tools to study the spatial distribution and temporal orchestration of mesoscopic events in the human brain. Our Collaborators will, through a dynamic ?push-pull? relationship, provide unique problems which drive the development of these tools, and in return guide us in the design and optimization of our toolbox for practical use in a variety of normal and disease settings. While there is still no formal consensus on the definition of mesoscopic within the neuroscience community, we take as our guide the spatial and temporal scales at which local groups of neurons act in coherent fashion ? in the cortex, this includes the spatial scale of columns and laminar structures (between ~0.1-1 mm), while in deeper structures includes the myriad of deep brain and brainstem nuclei. Preliminary data from our own center, and of course others throughout the world, now support the notion that we are on the threshold of being able to map, measure and perturb the human brain at these scales, and do so comprehensively across wide swaths of the human brain. Temporally too, recent advances suggest a convergence between temporal scales addressable with tools like fMRI, which can now investigate delta frequency coherent phenomena, and advanced electromagnetic tools to measure and perturb coherent electrophysiological activity at higher frequencies still. With this convergence in mind, the tools we proposed to develop within the TRDs of the CMM will provide our Collaborative and Service User community with the important ?missing links? between the advances in human cognitive neuroscience at the ?system level,? and the enormous strides in cellular level circuit functional characterization. Our Collaborators will bring their own unique challenges to help us define and further refine these tools, offering problems requiring distinct measures of human brain structural and functional properties in a variety of normal and disease settings. Our Service Users will utilize our tools to better understand human neural systems, and particularly human disease states from multiple sclerosis to Alzheimer?s, to depression and epilepsy. Finally, our Center will seek to disseminate these tools, through open-source software and hardware designs, industrial partnerships and ?hands-on? teaching courses for hardware, and to train a new generation of human neuroscientists in the use of our advanced tools to explore the human brain at this next frontier.

BTRC Administration ? Abstract The Center for Mesoscale Mapping (CMM) will be an integral part of the multidisciplinary research mission of the Athinoula A. Martinos Center for Biomedical Imaging, a collaborative research center of the Massachusetts General Hospital and the Harvard-MIT Division of Health Sciences and Technology. Joining the outstanding engineering and physical sciences, biological and neurosciences, and clinical investigation expertise for which these partner institutions are renowned worldwide, the Martinos Center is a unique research environment that provides vital synergy for the development of innovative imaging tools to advance brain science. The CMM and the Martinos Center will be intricately related. The administrative infrastructure of the CMM will draw on the robust infrastructure of the MGH Martinos Center for Biomedical Imaging to ensure efficient operation and provide multi-level support for the integrated research, training and dissemination activities of the CMM. The overall administrative framework of the CMM will support the specific aims of the BTRC, including coordinating administrative procedures to support cohesive research relationships between the grant?s Technology Research & Development Projects, Collaborative Projects and Service Projects, as well as to streamline CMM operation; providing administrative support for effective training in and dissemination of CMM-developed technologies; and ensuring compliance with all funding agency and institutional policies and reporting requirements by interfacing with Martinos Center and MGH administration, as well as with NIH and NIBIB program staff.

The goal of this proposal is to purchase a Bruker AV-Neo console to replace the out-of-date Siemens console of the 14T horizontal MR scanner (13cm bore), which has been dedicated to supporting the high-resolution anatomical and functional dynamic brain mapping of animals and ex-vivo human brain tissue imaging. The Martinos Center at the Massachusetts General Hospital has been at the forefront of developing advanced functional mapping methods, e.g., functional MRI, and implementing the cutting-edge MRI methods to bridge the basic and translational studies. To pursue the next-generation cutting-edge imaging methodology and prepare for the higher field MRI translational studies, there is an urgent need to improve our 14T MRI preclinical platform for high-resolution animal and ex vivo imaging. In particular, the proposed 14T MR console upgrade will boost the translational potentials of the novel methodology, e.g. the single- vessel fMRI and line-scanning fMRI, to bridge cellular and microvascular anatomy and functional dynamics from animal to human brains. Also, this proposal will support over 20 research projects funded by NIH, presenting critical translational efforts on the mechanistic studies of brain disorders including Alzheimer?s Diseases (AD), Parkinson?s Disease, cerebrovascular dementia, migraine, traumatic brain injury, and cardiac arrest (AC)-induced coma, as well as for the internal organ imaging of animal models with hepatitis and hepatic fibrogenesis. The highly synergistic and collaborative research projects outlined in our proposal can be summarized in three main themes: 1) Neurovascular dynamic signaling, 2) Cutting-edge neuroimaging methodology, 3) Multimodal mechanistic signatures of animal disease models. We have established the 14T- based multi-modal imaging platform to combine the high-resolution anatomical and functional MRI imaging with the emerging neuro-techniques, e.g. optogenetics, optical fiber-mediated biosensor recording of Calcium, Glutamate, etc, promoting novel mechanistic understanding of the complexity of brain function. The Bruker AV-Neo system will provide key technological innovations to improve the performance of the novel brain mapping methods, e.g. the single-vessel fMRI, line- scanning fMRI, RF slab-specific diffusion-weighted MRI, based on the state-of-the-art electronics and software design. Therefore, the proposed instrument upgrade would not only accelerate the progress of the listed projects but also facilitate the translation of cutting-edge MR methodologies as a truly multidisciplinary, regional resource for PHS funded investigators.