Truman R. Brown - US grants

This Program Project Grant consists of five Projects and two Cores designed to optimize the development of nuclear magnetic resonance technology for both basic cancer research and clinical applications. Three of the Projects concentrate on developing and utilizing ultra high resolution proton imaging procedures. Two of these follow the evolution of preneoplastic tissue to metastatic hepatocellular carcinoma; one in a chemical carcinogenic model in rats, the other in a viral hepatitis model in woodchucks. The remaining one evaluates the efficacy of NMR examinations for diagnosis of metastatic axillary lymph nodes. The other two Projects use primarily NMR spectroscopic methods to investigate the metabolic and physiological consequences of neoplastic transformation. The studies concern pH regulation in well defined cell lines transformed with oncogenes and the metabolism of a range of isolated arterially- perfused hepatomas. An Instrumental Support core provides the technical support to develop the necessary special purpose NMR probes and imaging surface coils required for these Projects. An Administrative Core provides budgetary control and clerical services for the PPG.

We propose to use 31P NMR spectroscopy in conjunction with proton and CT imaging to correlate changes in the anatomical appearance of soft tissue sarcomas following pre-surgical chemotherapy with physiological and metabolic information obtained from 31P spectra localized to the sarcoma. Patients with soft tissue sarcomas will undergo NMR proton imaging and 31P spectroscopic examination of the tumor and surrounding tissue, prior to the initiation of chemotherapy, during its course, and just before final tumor resection. The soft tissue sarcomas tend to be large tumors in the extremities easily accessible to NMR examination. In addition, biopsy and tissue samples will be available for extraction, enabling us to compare the metabolites observed in the extracted in vitro spectra with those observed in vivo. Spectroscopic observations, as well as the information from the proton images, will be correlated with the histopathological results on tumor type and responses, and with the long term patient survival. In vivo observations will be made using chemical shift imaging (CSI) techniques. These techniques allow simultaneous observation of large volumes of tissue with a relatively high resolution (Z-3 cm for 31P). The data will be analyzed by an automatic software procedure which allows for peak identification and quantification with automatic baseline estimation (PIQABLE). This automatic data analysis will be invaluable in dealing with the large quantities of spectra produced by 3-dimensional CSI observations. Extensions of the CSI methodology are proposed which use the information in the free induction decay during the period the phase encoding gradients are on. Methods for presentation of spectroscopic data as overlays on the proton images will be developed in order to fully utilize the range of metabolic information provided by the CSI observations and facilitate correlation of spectroscopic and image data.

The Society of Magnetic Resonance in Medicine was formed in 1980 by multidisciplinary basic and clinical scientists working in the fields of neclear magnetic resonance (NMR) spectroscopy and imaging, and electron spin resonance (ESR). The membership is comprised of many of the pioneers in in vivo NMR spectroscopy and imaging. A major purpose of the Society is to maintain strong basic and clinical science foundation which will lead to the most effective in vivo experimental and diagnostic studies. The Society has held six annual conferences thus far, and attendance has been consistent with the enthusiastic participation of the scientific community. Teaching sessions are held in association with the meeting for convenient exchange of the more elementary aspects of the field for both physicians and basic scientists. It is apparent that a major function of the annual meeting is the education of young scientists, M.D.'s and/or PH.D.'s To this end we seek support from NIH for student travel stipends as matching support to funds the Society will provide for this purpose. We believe student attendance at this meeting will continue to increase in 1988, and that without the matching support, young scientists will not have the interchange of new ideas and latest developments in the field. NMR has emerged as a powerful new technique with great clinical potential, and it is drawing researchers from many disciplines. Bringing together the finest researchers and the students of this rapidly evolving field will disseminate knowledge and enhance progress in important areas of medical research that bears on virtually every medical discipline.

We propose to use 31P NMR spectroscopy in conjunction with proton and CT imaging to correlate changes in the anatomical appearance of soft tissue sarcomas following pre-surgical chemotherapy with physiological and metabolic information obtained from 31P spectra localized to the sarcoma. Patients with soft tissue sarcomas will undergo NMR proton imaging and 31P spectroscopic examination of the tumor and surrounding tissue, prior to the initiation of chemotherapy, during its course, and just before final tumor resection. The soft tissue sarcomas tend to be large tumors in the extremities easily accessible to NMR examination. In addition, biopsy and tissue samples will be available for extraction, enabling us to compare the metabolites observed in the extracted in vitro spectra with those observed in vivo. Spectroscopic observations, as well as the information from the proton images, will be correlated with the histopathological results on tumor type and responses, and with the long term patient survival. In vivo observations will be made using chemical shift imaging (CSI) techniques. These techniques allow simultaneous observation of large volumes of tissue with a relatively high resolution (Z-3 cm for 31P). The data will be analyzed by an automatic software procedure which allows for peak identification and quantification with automatic baseline estimation (PIQABLE). This automatic data analysis will be invaluable in dealing with the large quantities of spectra produced by 3-dimensional CSI observations. Extensions of the CSI methodology are proposed which use the information in the free induction decay during the period the phase encoding gradients are on. Methods for presentation of spectroscopic data as overlays on the proton images will be developed in order to fully utilize the range of metabolic information provided by the CSI observations and facilitate correlation of spectroscopic and image data.

An open question is whether the metabolic changes associated with pathological states and their response to therapy can be observed by NMR spectroscopy. In this grant, we propose to develop Chemical Shift Imaging (CSI) techniques which will allow this question to be answered. To maximize the metabolic information which can be obtained in a clinical setting, procedures for acquiring spatially localized 31P and 1H spectra with the highest possible sensitivity will be integrated with new processing and display algorithms. The integration of these components will permit the metabolic information inherent in the spectra to be correlated with other clinical data, allowing the identification of the most significant spectral parameters. The sensitivity of the data will be improved by designing and building new rf coils, by installing proton decoupling for 31P spectroscopy and by extending water suppression techniques to use with 1H chemical shift imaging (CSI). New data processing procedures and software packages will also be developed for examination planning, automatic first pass analysis of the CSI data, quantifying individual spectra and producing metabolic images. The information in coil sensitivity maps, relaxation times and peak areas of individual spectra will be combined to produce absolute metabolic concentrations, which will then be correlated with the anatomy as depicted in the associated proton images. To test the procedures and build up a database of metabolite concentrations in normal tissue, 31P CSI will be applied to study muscle and brain of volunteers. In the case of brain, a comparison will also be made with the metabolic information provided by localized 1H spectroscopy. In the final years of the grant, the techniques will be applied to study two tumor systems: squamous cell carcinoma metastases of the neck and brain metastases. This will provide an opportunity to study tumor heterogeneity, to compare localized 31P and 1H spectra and to test the feasibility of applying our procedures in a clinical setting. As the procedures being developed in this grant are validated, they will be made available to other investigators so that they can be applied routinely in a clinical setting.

This Program Project Grant consists of 4 projects and 3 cores designed to optimize the utility of nuclear magnetic resonance spectroscopy in both basic research and clinical research. Three of the projects concentrate on studying specific metabolic pathways in well-controlled pathological states. One of these investigates the metabolism of isolated, arterially perfused hepatomas of varying degrees of malignancy. Another seeks to determine the metabolic causes for the elevated phospholipid metabolites observed in virtually all tumors and transformed cell lines. The third project proposes to develop and apply methodology with the highest possible sensitivity to acquire and display metabolic information in well localized 31P and 1H spectra from humans. The remaining project will measure changes in metabolite levels and energy metabolism in human muscle and brain brought about by cancer-induced cachexia and how these changes respond to parenteral therapy. The Chemistry Core provides synthetic organic chemistry support to the projects as well as extending their analytical procedures for extracts and developing non-NMR related techniques to enhance detection sensitivity. The Instrument and Computer Core provides both the technical support necessary to develop special purpose NMR coils and probes required in the projects, as well as essential computer support for the analysis and display of the complex datasets arising from the localized spectroscopy. An Administrative Core provides budgetary control and clerical services for the PPG.

DESCRIPTION: This application is from the FCCC. The 31-phosphorus (31-P) nuclear magnetic resonance (NMR) spectroscopy (MRS) resonance of human cancers in vivo reveals metabolic characteristics which differ from those of normal tissues. These include elevations in PME, PDE, and of cellular pH, and dimininution of PCr. Published studies show that MRS- derived pH and MRI-derived T2 relaxation time predict response of soft tissue sarcomas to radiation and hyperthermia, and that changes in PME's predict response of several different human cancers to chemotherapy and radiation. The applicant proposes a prospective trial to test the hypotheses that in vivo 31-P MRS can predict sensitivity or resistance to treatment inpatients with types of cancers especially well suited to determine the clinical utility of MRS in cancer management, in particular non-Hodgkin's lymphomas and locally-advanced primary breast cancers. This will be done by correlating response rate and disease-free survival to metabolic features in the baseline spectrum and to changes in the spectrum occurring early following initiation of treatment. This application is the central one of 8 interactive R01 applications from institutions cooperating to study over 1500 patients with non-Hodgkin's lymphomas, locally-advanced breast cancers,sarcomas, and carcinomas of the head and neck. Attention will be paid to patient selection, protocol management, technical quality control and statistical analyses. The state-of-the-art techniques used will be uniform across the 8 institutions and will include: (1) The use of dual-tuned proton/phosphorus surface coils to interrogate various tumor anatomical locations. (2) Proton-decoupling of phosphorus spectra to distinguish individual components of phospholipid metabolites in the PME and PDE regions. (3) Image-guided 3-dimensional chemical shift imaging to accurately localize 13P NMR spectra to tumor masses, and (4) Molar quantitation of metabolite concentrations in the tumors. This application also proposes to establish standards for cooperative MRS trials in other diseases and clinical settings, and seeks to pave the way for clinical trials in which MRS could be used to intervene in the selection of treatment regimens in individual patients with cancer.

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31/P magnetic resonance spectroscopy (MRS) of human cancers in vivo reveals metabolic characteristics which differ from those of normal tissues. These include elevations of phosphomonoesters (PME), phosphodiesters (PDE) and cellular pH, and diminished phophocreatine (PCr). Preliminary results in ongoing studies suggest that changes in PME's predict response of sarcomas to chemotherapy and that MRS-derived pH predicts response of soft tissue sarcomas to radiation and hyperthermia. The study we propose is a prospective trial in patients receiving neoadjuvant treatment of newly-diagnosed bone and soft tissue sarcomas. Attention will be paid to patient selection, protocol management, technical quality control and statistical analysis. State-of-the-art techniques will be used to optimize the metabolic information obtained. These include dual-tuned 1/H-/31P surface coils to access the wide variety of anatomic locations of sarcomas; 1/H decoupling of 31/P to distinguish individual components of phospholipid metabolites in the PME and PDE regions; image-guided 3-dimensional chemical shift imaging to accurately localize 31/P NMR spectra to tumor masses; and molar quantitation of metabolites. We will test the hypothesis that in vivo 31/P MRS can predict sensitivity or resistance to treatment by correlating response rate and disease-free survival to metabolic features in the baseline spectrum and to changes in the spectrum occurring early following initiation of treatment. Positive results in this study would pave the way for a clinical trial in which 31/P MRS would be used to intervene in the selection of treatment regimens in individual patients with sarcomas.

The most common site of metastasis from breast cancer is bone. A major problem in treating bone metastases is the lack of objective measures of response to systemic chemotherapy or hormonal therapy. This occurs because abnormalities in bone scintigraphy and radiography, which are based on secondary manifestations of metastases (reactive new bone formation or bone destruction) are not present in all patients, when present indicate relatively advanced disease, and may or may not change when the cancer responds to or progresses during treatment. Thus patients with unresponsive cancers may suffer unnecessary toxicity from prolonged treatment; patients with responding cancers may have treatment discontinued prematurely; and many patients are ineligible for clinical trials of new treatments because they lack objective indicators of response. Our preliminary study in 33 patients shows that MRI directly visualizes metastatic deposits within bone marrow, does not rely on secondary manifestations, and reveals multiple small metastases not evident in radiography or scintigraphy. We propose to test the hypothesis that MRI is a reliable, objective means to assess response of bone and bone marrow metastases of breast cancer to treatment with systemic therapy. Our approach is to conduct a prospective trial in which concordance with other indices of response is examined and clinical endpoints (duration of complete response, time to progression, and survival) are used to determine if MRI response categories are significant predictors of prognosis.

This Program Project Grant consists of three Projects and four Cores designed to optimize the utility of nuclear magnetic resonance spectroscopy in both basic and clinical research. The first project proposed to develop and apply methodology with the highest possible sensitivity to acquire and analyze metabolic information in well localized 31P and 1H spectra from humans. The next Project will study patients with head and neck squamous cell carcinomas whose tumors will have the their p02 levels measured with an Eppendorf nucroelectrode. 1H decoupled 31P CSI spectra will also be obtained from their tumors and correlated with the hypoxic status of the tumor. The final Projects concentrate on studying specific metabolic pathways in well-controlled cell cultures in order to determine the metabolic causes for the elevated phospholipid metabolites observed in virtually all tumors and transformed cell lines. The Chemistry Core provides synthetic organic chemistry support to the projects as well as extending their analytical procedures for extracts and developing non-NMR related techniques to enhance detection sensitivity. The Instrument and Computer Core provides both the technical support necessary to develop special purpose NMR coils and probes required in the projects, as well as essential computer support for the analysis and display of the complex datasets arising from the localized spectroscopy. The Data Analysis Core will provide automatic spectral quantitative software to all the projects. An Administrative Core provides budgetary control and clerical services for the PPG.

Our recent 31P NMR studies of lymphomas in vivo and of chronic lymphocytic leukemic cells in vitro show that human B-lymphoid malignancies have a patter of phospholipid metabolites characterized by a high ratio of phosphoethanolamine to phosphocholine and very low amounts of glycerophosphoethanolamine and glycerophosphocholine. We hypothesize that this pattern results in large part from a sustained activation of one or more phospholipases C or D acting on phosphatidylethanolamine (PE). We have observed further that an early treatment-induced decrease in the phosphoethanolamine signal intensity predicts response of an individual lymphoma to whatever treatment was initiated. We hypothesize that this phenomenon is a manifestation of the susceptibility of the lymphoma cells to undergo treatment-induced apoptosis, and that it reflects the modulation of a process specific for PE metabolism. We propose to test these hypotheses using 3 different human B-lymphoid malignancy cell lines which are models of the grades of NHL found in vivo. They will be studied under conditions in which their phospholipid metabolite pattern resembles that of lymphomas in vivo. The hypothesis that these cells have sustained activation of a phospholipase C or D will be tested by examining catabolism of radiolabelled phospholipids, and aspects of phospholipid synthesis will be examined in NMR studies of perfused cells. The effects of treatment- induced apoptosis on phospholipid synthesis and degradation will be studied using these techniques along with 31P NMR spectroscopy. This Project interacts closely with the Chemistry Core in the exchange of developing techniques and insights. The results of this project should provide a better understanding of the biochemical and biological bases for the phospholipid metabolic characteristics of lymphomas observed in vivo in clinical settings.

The Data Analysis Core is responsible for providing the investigators in this Project Grant with the capability of analyzing large datasets consisting of hundreds of spectra in efficient and reproducible ways. To this end, we will implement and automated easily used Principal Component Analysis (PCA) procedure to provide a quantitative analysis of spectral peak amplitudes as well as develop techniques to extract coherent patterns in CSI and kinetic datasets. A variety of applications are presented as preliminary results which suggest that this technique will be very effective in providing quantitative information from datasets in a very efficient way.

DESCRIPTION (provided by applicant): 1H nuclear magnetic resonance (NMR) is widely used to investigate the metabolic state of biological samples. Its non-invasive nature and ability to detect multiple compounds allow it to follow complex biochemical processes over time at a high level of detail leading to its use in "metabolomics" or characterization of the metabolite response of living systems to pathophysiological stimuli or genetic modification. It generates spectra with a large number of resonances from hundreds of related samples. The use of pattern recognition techniques here have been restricted by two factors: 1) small systematic variations in frequency caused by small differences in temperature, pH, etc. and 2) use of principal component analysis (PCA) for the identification of the mathematical components of the variation in the dataset, rather then true physical sources for dynamic changes. The variations in frequency have led to "binning" the spectra to only a few hundred points while the use of PCA to identify underlying patterns in the datasets makes finding physically meaningful metabolic patterns hard. In this R33 we address these problems by robust pretreatment of high resolution NMR data and then applying Bayesian Spectral Decomposition (BSD) and constrained Non-negative Matrix Factorization (cNMF) to uncover the underlying metabolic patterns that describe the change in the system. There are five main Specific Aims Specific Aim I: Develop a semi-automated preprocessing procedure for series of high resolution 1H NMR spectra of urine to improve spectral quality to enable PR procedures to identify any underlying biochemically relevant spectral patterns. Specific Aim II: Implement Bayesian Spectral Decomposition (BSD) as a practical easy-to-use spectral analysis procedure. Specific Aim III. Implement constrained Non-negative Matrix Factorization (cNMF) as a practical easy-to-use spectral analysis procedure Specific Aim IV. Implement BSD as parallel code on a Linux cluster. Specific Aim V. Apply BSD and cNMF to analyze a series of NMR spectra of urine acquired from toxicology studies of rats and mice that have been preprocessed by the techniques of Specific Aim I.

The Brain Imaging Core has been added to this project because of the extraordinary developments in brain imaging using MRI over the last five years. Not only do the images provided excellent anatomical information but we can now obtain local metabolic information as well. The combination of the two types of information has the potential of serving as new biomarkers of risk and disease progression in Alzheimer's disease, particularly when used in conjunction with the other markers we have identified in previous cycles of this grant. The non-invasive character of the exam is particularly important for prospective epidemiological studies in an elderly population as are proposed here. The Core will be using a t.5T research scanner, part of the recently developed neuroimaging program at Columbia and applying both standard imaging procedures and techniques to measure local basal metabolism in the brain based on the relationship between metabolism and cerebral blood volume (CBV) which will be determined from Gadolinium difference images. We have extended this technique to allow measurement of the CBV in hippocampal subregions. The standard anatomical images will be sent to Dr. Charles DeCarli at UC Davis for volumetric analysis (total cerebral volume, volume of white matter hyperintensities, CSF volume, and volumes of the hippocmnpus and entorhinal cortex and stroke location and volume). The basal metabolic data will be estimated from local CBV calculated from difference images pre and post Gadolinium injection for subregions of the hippocampus (entorhinal cortex, subiculum, CA 1 and the dentate gyrus). The resultant volumetric and metabolic data will be entered into an Excel file and forwarded to EDMS Core. There are five specific aims: l. Acquire high quality anatomic and CBV images from the WHICAP cohort. 2. Archive the MRI data onto a RAID system and individual subject optical disks. 3. Transfer the anatomical images to Dr. Charles DeCarli at UC, Davis for volumetric analysis. 4. Calculate CBV in the subregions of the hippocampus and globus palladus. 5. Collect data from Dr. DeCarli's analysis and the basal metabolic estimates from Specific Aim 3 and input them into the project database maintained by the EDMS Core.

DESCRIPTION (provided by applicant): 1H nuclear magnetic resonance (NMR) is widely used to investigate the metabolic state of biological samples. Its non-invasive nature and ability to detect multiple compounds allow it to follow complex biochemical processes over time at a high level of detail leading to its use in "metabolomics" or characterization of the metabolite response of living systems to pathophysiological stimuli or genetic modification. It generates spectra with a large number of resonances from hundreds of related samples. The use of pattern recognition techniques here have been restricted by two factors: 1) small systematic variations in frequency caused by small differences in temperature, pH, etc. and 2) use of principal component analysis (PCA) for the identification of the mathematical components of the variation in the dataset, rather then true physical sources for dynamic changes. The variations in frequency have led to "binning" the spectra to only a few hundred points while the use of PCA to identify underlying patterns in the datasets makes finding physically meaningful metabolic patterns hard. In this R33 we address these problems by robust pretreatment of high resolution NMR data and then applying Bayesian Spectral Decomposition (BSD) and constrained Non-negative Matrix Factorization (cNMF) to uncover the underlying metabolic patterns that describe the change in the system. There are five main Specific Aims Specific Aim I: Develop a semi-automated preprocessing procedure for series of high resolution 1H NMR spectra of urine to improve spectral quality to enable PR procedures to identify any underlying biochemically relevant spectral patterns. Specific Aim II: Implement Bayesian Spectral Decomposition (BSD) as a practical easy-to-use spectral analysis procedure. Specific Aim III. Implement constrained Non-negative Matrix Factorization (cNMF) as a practical easy-to-use spectral analysis procedure Specific Aim IV. Implement BSD as parallel code on a Linux cluster. Specific Aim V. Apply BSD and cNMF to analyze a series of NMR spectra of urine acquired from toxicology studies of rats and mice that have been preprocessed by the techniques of Specific Aim I.

DESCRIPTION (provided by applicant): The Experimental NMR Conference (ENC) is the premier annual scientific meeting devoted to technical aspects and applications of nuclear magnetic resonance spectroscopy, including solution-state, solid-state, and imaging methods and applications in physics, chemistry, materials science, and biology. The 46th ENC will be held April 10, 2005 through April 15, 2005 in Providence, RI. Attendance at the meeting will be approximately 1,400 scientists, including graduate students, postdoctoral fellows, and senior scientists, from the U.S. and other countries. Approximately 250 of the attendees are graduate students. The meeting is comprised of plenary and poster sessions. Plenary sessions include invited speakers and promoted poster talks. Approximately 45 invited plenary talks and 20 promoted poster talks are scheduled during the meeting. Approximately 600 posters are presented during the meeting. The focus of the meeting is new technical developments and applications of nuclear magnetic resonance spectroscopy. The ENC is the only major conference in the U.S. in which all aspects of the field, including solution-state, solid-state, and imaging methods, are presented. For many years the ENC has funded a student travel stipend program to enable graduate students to attend the ENC. Historically, funds have been obtained from two sources: a percentage of conference registration fees and contributions from companies. Attending the ENC is an important supplement to graduate education in NMR spectroscopy: the ENC provides a graduate student with unparalleled exposure to the full range of the field and its practitioners and enables students to present their own work to the widest possible audience. At present, only some 65 students (both U.S. and international), representing 25% of the graduate student attendees, can be provided with travel stipends. Support is requested from the National Institutes of Health to enable the ENC to expand the student travel stipend program by approximately 10 to 15 students. This would permit an increased number of deserving students to attend the conference.

DESCRIPTION (provided by applicant): 1H nuclear magnetic resonance (NMR) is widely used to investigate the metabolic state of biological samples. Its non-invasive nature and ability to detect multiple compounds allow it to follow complex biochemical processes over time at a high level of detail leading to its use in "metabolomics" or characterization of the metabolite response of living systems to pathophysiological stimuli or genetic modification. It generates spectra with a large number of resonances from hundreds of related samples. The use of pattern recognition techniques here have been restricted by two factors: 1) small systematic variations in frequency caused by small differences in temperature, pH, etc. and 2) use of principal component analysis (PCA) for the identification of the mathematical components of the variation in the dataset, rather then true physical sources for dynamic changes. The variations in frequency have led to "binning" the spectra to only a few hundred points while the use of PCA to identify underlying patterns in the datasets makes finding physically meaningful metabolic patterns hard. In this R33 we address these problems by robust pretreatment of high resolution NMR data and then applying Bayesian Spectral Decomposition (BSD) and constrained Non-negative Matrix Factorization (cNMF) to uncover the underlying metabolic patterns that describe the change in the system. There are five main Specific Aims Specific Aim I: Develop a semi-automated preprocessing procedure for series of high resolution 1H NMR spectra of urine to improve spectral quality to enable PR procedures to identify any underlying biochemically relevant spectral patterns. Specific Aim II: Implement Bayesian Spectral Decomposition (BSD) as a practical easy-to-use spectral analysis procedure. Specific Aim III. Implement constrained Non-negative Matrix Factorization (cNMF) as a practical easy-to-use spectral analysis procedure Specific Aim IV. Implement BSD as parallel code on a Linux cluster. Specific Aim V. Apply BSD and cNMF to analyze a series of NMR spectra of urine acquired from toxicology studies of rats and mice that have been preprocessed by the techniques of Specific Aim I.

[unreadable] DESCRIPTION (provided by applicant): NMR spectroscopy is the most promising non-invasive method for assessing the biochemical state of the brain associated with different pathologies, including neurodegenerative and psychological disorders, cancer, inborn errors of metabolism, as well as for understanding the role of metabolites in the working brain. Incorporating metabolic information with the other modalities of neuro-imaging, however, is quite challenging. Chemical Shift Imaging acquires localized spectra in the brain in volumes as small as 0.4 cc, resulting in datasets containing hundreds of spectra. The goal of this grant application is to enhance software tool, 3D interactive Chemical Shift Imaging (3DiCSI), for comprehensive application to neuro-imaging data analysis. 3DiCSI combines data visualization, spectral processing, spectral localization and estimation, and spectral quantification together with spectral pattern recognition techniques, such as Principal Component Analysis and constrained Non-negative Matrix Factorization. The proposed developments will improve the automatic importation of raw data by including file formats from all scanner brands as well as interface spectroscopy data with other neuro-imaging software tools. The standardization of data exportation and providing multi- platform support for the program will promote the data-sharing in the community and allow for dynamic collection of spectral data for creation of annotated database of brain metabolic patterns. The ability for a user to extend the functionality of the program will render 3DiCSI as a research platform providing data visualization, preprocessing and multivariate analysis which can be used to enhance an individual researcher's analytical procedures. Parallelization of the data processing routines and extending the spectral pattern discovery procedures will allow for real time identification and interpretation of aberrant spectral signature, related to type and state of disease, particularly important for the clinical application of 3DiCSI. Generation of comprehensive report summarizing the spectroscopy exam will be also essential for communicating the results. Support for automatic online program update download and improved documentation will ensure utilization of the program to its greatest potential. These developments will greatly improve the interoperability, adoptability and usability of 3DiCSI and facilitate the utilization of spectroscopy in neuro-imaging applications. [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Non-Hodgkin's lymphoma (NHL) is the fifth most common type of cancer in the United States, and diffuse large B cell lymphoma (DLBCL) is its most common subtype. Until recently DLCBL was rapidly and inevitably fatal, but the new standard of treatment with multi-drug immuno-chemotherapy combinations makes this form of cancer potentially curable in 40% of patients. The last hope for the majority for whom standard treatment will fail lies in more radical therapies such as bone marrow transplant. These alternate treatments are more risky, especially for patients already weakened by a failed attempt at standard immuno-chemotherapy. There is thus a great need for information that could allow oncologists to individualize treatment and immediately begin radical therapy in those for whom standard treatment is likely to fail. We believe our non-invasive measurement of NHL tumor metabolism with magnetic resonance spectroscopy (MRS) can provide this information. During previous periods of grant support, we have obtained promising initial results showing that the pre-treatment metabolic ratio of phosphoethanolamine (Etn-P) and phosphocholine (Cho-P), normalized by the tumor content of nucleotide triphosphates (NTP), can sensitively and specifically predict treatment failure in DLBCL. The first aim for our multi-center study is to test our hypothesis that the [Etn-P + Cho-P]/NTP ratio is significantly correlated with treatment outcome in DLBCL. In addition to confirming our previous results with 31P MRS at the 1.5T field strength in an independent sample of patients, we also seek to extend these findings by studying the metabolism of DLBCL tumors with 31P at 3.0T, and also investigating absolute choline levels in DLBCL with 31P and 1H at both 1.5T and 3.0T. Our second aim is to follow up on initial indications that the significance of the correlation between the [Etn-P + Cho-P]/NTP ratio and treatment outcome is widely applicable to all forms of NHL and not merely the DLBCL subtype. We will approach this aim by accruing sufficient patients to analyze each subtype independently, using the 1.5T methods that are most directly applicable to the contemporary clinical environment. The proposed research is the final step leading a directed-therapy clinical trial and the culmination of an unprecedented program of translational research in MRS. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Arterial spin labeling (ASL) has many advantages for the measurement of cerebral blood flow (CBF) and regional brain perfusion. Such measurements are significant for research and diagnosis and treatment of stroke, ischemia, brain tumors, and dementia. ASL is non-invasive, inexpensive, and produces high-resolution images that are easily compared with other anatomical and functional magnetic resonance imaging (MRI) scans acquired as part of the same session. The ASL method involves labeling inflowing arterial spins by inverting them at a plane proximal to the imaging volume. A major factor in the calculation of CBF is the transit time for the labeled protons to pass from the imaging plane and into the labeling plane. Most standard ASL sequences suffer from the limitation that they cannot measure transit times directly. Instead, they rely on a method of factoring out the effect of travel times that is introduces multiple sources of confound and limits signal-to-noise ratio, especially in white matter. Furthermore, standard ASL measurements are unable to determine whether the changes detected are truly reflections of changes in flow or the result of the alterations in transit times known to be involved in neural activation and stroke. In this proposal, we describe a novel method of arterial spin labeling that is able to directly measure transit times. Our method offers the advantages of standard ASL while removing some of its limitations. This is made possible by labeling the arterial spins according to a pseudo random sequence. The mathematical properties of the sequence used for pseudo random amplitude modulation, or PRAM, allow recovery of all the transit times present in the imaged tissue as part of a single integrated acquisition. Implementation of this method should provide novel insights into the details of cerebral blood flow at both the macroscopic and microscopic levels. Detailed specific aims are: Specific Aim 1a: Implement the pseudo random arterial modulation (PRAM) scheme on a Siemens 3T Trio scanner. Specific Aim 2: Validate the PRAM sequence developed in SA 1 using standard spin tagging and ASL techniques in phantoms. Specific Aim 3: Extend the validation studies to human volunteers undergoing visual stimulation by comparing the PRAM results to those acquired by standard PASL sequences.

bioimaging; brain morphology; Communities; Complex; Computer software; Data; Development; Equipment; Exercise; experience; Housing; Human Resources; Image; Image Analysis; Imaging Device; Individual; interest; Intervention; Lead; Mentors; Metabolic; Metabolism; Methodology; Methods; neuroimaging; neuromechanism; novel; Patients; Recovery of Function; Regimen; Rehabilitation Research; Rehabilitation therapy; relating to nervous system; Research; Research Design; Research Personnel; Resources; response; Series; software development; South Carolina; stroke; stroke recovery; stroke rehabilitation; Techniques; Technology; tool; Training;

? DESCRIPTION (provided by applicant): This R21/R33 grant will design and build a neural imager/stimulator which will integrate EEG, TMS and fMRI into a single instrument in the R21 phase. This will enable EEG and fMRI to be acquired simultaneously in conjunction with the application of TMS pulses. This instrument will test the hypothesis that TMS pulses applied in synchrony with the brain's internal rhythms will have greater local and distributed effects than will non-synchronized stimulation and specifically whether knowing and understanding the brain's rhythms and stimulating with this knowledge will have larger brain effects than the current state of the art, where stimulation is largely done without knowledge of internal brain state. The R21 phase will test these in normal subjects after the full real-time feedback system is developed. In the R33 phase we will test whether synchronized TMS will be a successful treatment in a high percentage of drug resistant depressed patients, and will result in better clinical outcomes than will non-synchronized stimulation, which is currently employed. The detailed Specific Aims to accomplish these goals are: R21 phase Specific Aim1: Integrate an EEG system with our existing simultaneous TMS and fMRI scanner so the final instrument is able to acquire and conduct simultaneous EEG-fMRI-TMS measurements. Specific Aim2: Develop the necessary software and interface hardware to detect and use in real-time the alpha phase and/or frequency to provide real-time closed loop control of the TMS pulse timing. Specific Aim 3: Show in a cohort of normal subjects that there is significant variation of rACC inhibition as the timing of TMS pulses applied to the DLPFC are varied with respect to the phase and frequency of an individual's alpha rhythms. R33 phase Specific Aim 1: Integrate a similar EEG system with our treatment TMS scanner with similar feedback circuitry as that in SA 3 in the R21. Specific Aim 2: Carry out a 4 week trial of anti-depressive therapy randomized between optimum timed TMS and standardized non-synchronous TMS in a cohort of depressed patients to estimate the success rate of such an optimized treatment.

The Neuroimaging Core (NI) provides access to state-of-the art neuroimaging facilities and methodologies. COBRE funds will support a Bioengineer (shared with the BSTIM Core) who will oversee the technical aspects and develop new methods to interface image acquisition with stimulation and rehabilitation techniques; a full- time Image Technician who will provide training and assistance for analysis and interpretation of complex measurements; partial effort of an EEG Technician who will provide guidance in techniques for high density EEG and assist with data analyses; and dedicated effort for senior faculty who will provide mentoring and training in rigor, reproducibility and interpretation as well as methods development for human and animal studies. Specific aims are to: (1) Provide COBRE investigators with turnkey access to modern neuroimaging tools to investigate stroke-recovery related changes in brain morphology, connectivity, metabolism and function; (2) Develop innovative tools to observe the detailed neural response (both short- and long-term) to diverse interventions; 3) Generate high quality, reproducible, quantitative data to help identify neuroimaging ?biomarkers? and thereby become a leader in forming large multi-system quantitative data sets for inclusion in the COBRE Comprehensive Multidisciplinary Database (CMD) as well as national and international data sharing efforts; and 4) Mentor and train COBRE investigators in the acquisition and analysis of complex neuroimaging data so they can investigate and exploit inherent plasticity and develop and translate novel mechanism-based, experience-dependent interventional methods. Continuous progress toward these aims will establish the NI Core as a premier resource in the integration of neuroimaging into stroke rehabilitation studies at MUSC, as well as nationally and internationally. The NI Core will facilitate investigators? access to structural and functional imaging methods such as blood oxygen level dependent (BOLD) magnetic resonance spectroscopy (MRS), arterial spin labeling (ASL), and high density electroencephalography (EEG), enabling them to ask important research questions such as tissue volume associated with the stroke and adaptive plasticity, stroke pathology, correlates of basal metabolism, local estimates of cellular complexity, regional responses to localized brain stimulation and corresponding functional responses. The NI Core?s multimodal, cross-disciplinary, integrative nature encourages collaborative innovation. The ability to use transcranial magnetic stimulation within the scanner (i.e., interleaved TMS/fMRI) makes MUSC one of very few places where investigators can directly examine immediate and longer- term effects of brain stimulation interventions on brain activity and hemodynamics, and investigate the causal nature of induced activity in cortical and subcortical nodes of a brain network. In addition, 7T small animal scanning and two-photon microscopy systems provide sensitive translational tools to investigate mechanisms underlying rehabilitation and cortical stimulation enhancement of neural plasticity and stroke recovery in animal models.