Ponnada Narayana - US grants

Localized spin lattice relaxation time (Tl) measurements of the individual chemically shifted nuclear magnetic resonance (NMR) peaks may afford better tissue characterization. These measurements require methods to accurately and efficiently localize the region of interest. A number of such methods have been reported in literature, out of which four show a great deal of promise. These are 1) depth resolved surface coil spectroscopy, 2) localization based on imaging principles, 3) volume selective excitation (VSE) and 4) image selected in vivo spectroscopy (ISIS). The proposed project will 1) implement these four methods on the imager/spectrometer built in our laboratory, 2) compare these methods for their relative accuracies and efficiencies using phantoms, 3) develop and implement pulse sequences to measure local Tl based on inversion recovery, and 4) determine the optimum methods for local Tl measurements under a given set of experimental conditions using phantoms. Good localization was achieved on our system, using the VSE method on phantoms. These studies have also pointed out the need to shorten the gradient settling times. This will initially be achieved by shaping the current through the gradient coils. It is expected that these studies will enable us to accurately measure local relaxation times in-vivo for a better tissue characterization.

In vivo high resolution proton MR spectra from a region of interest indicated by the image offer an unprecedented opportunity to obtain detailed metabolic and biochemical information non-invasively. In order to realize this objective, it is essential to be able to 1) localize the region of interest as indicated by the image, 2) suppress the strong resonances from water and lipid protons so that weak resonances from important metabolites and biochemicals can be observed and 3) reduce the spectral complexity and pick up resonances of interest by using editing techniques. The aim of this proposed project is to develop a number of pulse sequences which incorporate all these features and assess their performance using phantoms. All the proposed work will be carried out on a 2T, 25 cm clear horizontal bore imager/spectrometer designed and built in our laboratory. The volume localization method that will be used in these studies is based on imaging principles. This method is independently developed by us and Luyten et al (J. Mag. Reson. 67: 148, 1986). A number of pulse sequences which combine the localization and the suppression of resonances originating from water and lipid protons are proposed. These sequences will be evaluated using phantoms and optimum sequences will be identified. Editing techniques which use 1H homonuclear double resonance difference spectroscopy will be combined with water suppressed localized spectroscopy sequence to reduce the spectral complexity and pick up selected resonances. It is expected that these studies will allow the detection of diseases at an early stage and enable us to monitor the effects of therapeutic treatment.

Every year in the United States 10,000 to 20,000 young adults suffer permanent disability as a result of spinal cord injury. However, a proper evaluation and characterization of spinal cord injury is hindered by lack of a non-invasive radiologic modality. In these studies we propose to critically assess the role of magnetic resonance (MR), which includes both magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) , in the non-invasive diagnosis and prognosis of spinal cord injury. The proposed studies will be performed on three types of injuries with different severity in a rodent model with histopathological profiles similar to those seen in humans. The MRI-inferred extent and location of hemorrhage, edema and residual cord tissue (based on fast spin echo volume imaging and three-dimensional image analysis) will be validated with quantitative histology performed on the same animals. The MRS-determined changes in the concentration of N-acetyl aspartate (NAA) and lactate as a result of injury to the spinal cord will be compared with those determined using standard biochemical techniques. Both these studies will be performed at seven time points following the cord injury. In addition, MR results will be compared and correlated with functional (behavioral and electrophysiological) studies performed longitudinally. These studies could provide non-invasively additional and important information for predicting neurologic outcome following spinal cord injury and help customizing treatment on an individual basis in humans.

Magnetic resonance imaging (MRI) is the most sensitive radiologic modality in visualizing multiple sclerosis (MS) plaques. However, the monotonous appearance of many lesions limits the usefulness of a single MRI in distinguishing active lesions from inactive ones. The proposed longitudinal studies are designed to utilize state-of-the-art volumetric image analysis and image-guided in vivo proton magnetic resonance spectroscopy (MRS) in combination with the paramagnetic contrast agent gadolinium diethylentriaminepentaacetic acid (GdDTPA) for distinguishing different stages of MRI-defined and clinically correlated disease activity. Volumetric image analysis performed on dual echo thin slices (3 mm) with no interslice gap will allow quantitation of total lesion burden as well as volumes of individual plaques independent of small unavoidable errors in repositioning the patients on serial scans. The number and degree of enhancement of plaques will also be quantified using the image analysis. Multivoxel proton MRS will be performed at short-echo times to visualize lipids and other membrane breakdown products from the plaque-containing as well as adjacent-tissue with a volume resolution on the order of 2 cc. MRS data will be quantitatively analyzed to critically assess the role of lipids, N-acetyl aspartate (NAA) and other MR-visible neurochemicals in the characterization of MS plaques. Linked GdDTPA MRI and MRS should allow us to determine the MRS-defined changes in the neurochemicals in relation to acute changes in regional vascular permeability. Computed Relaxation images should allow the detection of plaques even when they are too small to be resolved on MRI or prior to GdDTPA enhancement. Many of the patients will be scanned at intervals of four weeks up to a period of six months. Magnetic resonance results will be correlated with clinical status. These multi-pronged MA studies should allow us to characterize and follow the evolution of MS plaques and improve our understanding of the pathophysiology of MS. A further significance of these studies is that they may enable us to follow objectively and quantitatively the efficacy of drugs in the treatment of MS.

This application seeks partial funding for purchasing a 7 Tesla/30 cm bore magnetic resonance scanner for in vivo imaging and spectroscopy of animals. This scanner will be housed in the University of Texas-Houston Medical School, which is located in the Texas Medical Center, home of four major research institutions and five hospitals. This scanner can accommodate animals ranging from mice to rhesus monkeys. In addition to the normal standard imaging gradient coils (maximum gradient strength of 100 mT/m; slew rate of 200 mu's), this scanner will be equipped with a mini-imaging system (maximum gradient field of 200 mT/m; slew rate of 80 mu's) and RF probes for imaging structures such as spinal cords, and small animals such as mice with high resolution and high speed. The strong and fast gradients allow the implementation of advanced techniques such as diffusion tensor imaging (DTI), functional MRl (fMRI), and perfusion, all based on ultrafast imaging. The scanner will have all the RF coils and preamplifiers necessary for acquiring localized in vivo multi-nuclear (1H, 13C, 19F, 23Na, and 31P) spectroscopic data from relatively small volumes. The high field along with a high performance gradient system should allow the implementation of a variety of sophisticated in vivo imaging and spectroscopic techniques. In the current application five major users who are PI's on one or more MH grants and two minor users are identified. Seven projects that utilize this scanner are described. These are: l) spinal cord injuries in rodents, 2) brain structure-functional relationship in rhesus monkeys, 3) calcium blockers and related therapy for cerebral ischemia in rodents, 4) mechanism of memory deficits following brain injury in rodents, 5) therapeutic hypothermia for traumatic brain injury in rodents, 6) signaling in skeletal muscle hypertrophy in rodents, and 7) atherosclerosis and vascular biology using ex vivo tissues and phantoms. There are also a number of other investigators who are interested in using this facility to enhance their research. Institutional commitment and plans for long term maintenance of this instrument are documented. To the best of the PI's knowledge, this will be the only facility of its kind in the South West part of the country.

DESCRIPTION (provided by applicant): This application seeks funding for a 7 Tesla, 30 cm bore magnetic resonance (MR) scanner for in vivo imaging and spectroscopy of small animals. This scanner will be housed in the University of Texas-Houston Medical School, which is located in the Texas Medical Center, home of four major research institutions and five major hospitals. Small animals ranging from mice to rhesus monkeys can be studied with this scanner. This instrument will be equipped with three imaging gradient coils that are capable of generating maximum gradient strengths of 200 mT/m, 400 mT/m, and 950 mT/m with slew rates ranging from 80 ps to 200 ps. The strong and fast gradients allow implementation of advanced techniques such as diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), and perfusion, all based on ultrafast imaging. The high field along with a high performance gradient system should allow the implementation of a variety of sophisticated in vivo imaging, including MR angiography (MRA) and spectroscopic techniques at short echo times. Three volume resonators of varying sizes (152 mm, 112 mm, and 35 mm id) will be included with this scanner. Multiple tuned RF coils and receivers necessary for performing in vivo, localized (single voxel and multi-voxel) multi-nuclear (1H, 13C, 19F, and 31P) magnetic resonance spectroscopy (MRS) will also be included. In the current application eight major projects are described. The projects are: (1) spinal cord injuries in rats; (2) chronic pain in spinal cord injury in rats; (3) brain structure-functional relationship in rhesus monkeys; (4) calcium blockers and related therapy for cerebral ischemia in rats; (5) etiology of cellular damage after experimental stroke in rats; (6) role of ACC2 in the regulation of fatty acid oxidation and lipid metabolism in mice; (7) MRI and magnetic resonance spectroscopy (MRS) studies in genetically engineered mice for a rational interpretation of the observed dynamic neurochemical changes and directional water diffusion in multiple sclerosis (MS) in humans; (8) genetic approaches to mitochondrial VDAC function in mice; (9) vulnerable atherosclerotic plaques in Apo-E deficient mice; and (10) glucose metabolism in central and peripheral systems in rats. Eight of these ten projects are based on NIH funded grants and the other two are federally funded studies. Institutional commitment and plans for long term maintenance of this instrument are documented. Organizational and financial plans for administering and maintaining the scanner are described. To the best of the PI's knowledge, this will be the only facility of its kind in Houston and the Southwest part of the USA.

DESCRIPTION (provided by applicant): This application seeks partial funding from NIH and NSF for purchasing a 3 Tesla, whole body magnetic resonance scanner for in vivo imaging (MRI) and spectroscopy (MRS) in humans and nonhuman primates. The scanner will be housed in the University of Texas Medical School at Houston, which is located in the Texas Medical Center, home of four major research institutions and five hospitals. This scanner will be equipped with body and head RF coils and high performance gradient system that is capable of producing maximum gradient amplitudes of 40 mT/m with a slew rate of 200 mT/m/s. In addition, it will incorporate five-second order room temperature shims for improved field homogeneity. This high performance system will allow us to implement advanced MR imaging techniques such as diffusion tensor imaging (DTI), functional MRI (fMRI), and spectroscopic imaging (MRSI). Processing software for DTI, fMRI, and MRSI (2D, 3D, multislice and with a variety of k-space scanning techniques) will be included with the scanner. A full research agreement with the manufacturer will be executed for access to all the source codes for the pulse sequences and reconstruction algorithm to modify the existing sequences and implement newer sequences on the scanner. These will be made available to all the users. In addition, the scanner will provide access to the raw data for testing advanced image processing techniques. This high field and high performance MR scanner will be used for investigating 1) various neurological disorders, 2) techniques for improving learning and development in normal school age children by fusing information from MRI and MEG, and 3) advanced automatic image processing. The neurological disorders that will be investigated include neurodevelopmental disorders in humans and nonhuman primates, psychiatric disorders, and demyelinating diseases such as multiple sclerosis. Twenty-one projects by fourteen users who are Pl's on NIH and NSF funded grants with significant MR component have been identified. While the main thrust of the proposed projects is neuroimaging, we anticipate that future projects would include body imaging, particularly cardiovascular imaging. Strong institutional commitment and financial plans for operating the scanner, particularly the long-term maintenance, are described.

[unreadable] DESCRIPTION (provided by applicant): Angiogenesis occurs in response to traumatic spinal cord injury (SCI). However, the role of angiogenesis in SCI is controversial. Based on our preliminary in vivo longitudinal magnetic resonance imaging (MRI), neurobehavioral, and end point histology studies, we hypothesize that angiogenesis is beneficial to recovery from SCI. We propose to verify this hypothesis by modulating the angiogenic activity by acute and long term administration of vascular endothelial growth factor (VEGF; for promoting angiogenesis) and anti-VEGF (neutralizing the effects of endogenous VEGF) in experimental SCI. The effect of these compounds will be assessed by combining in vivo longitudinal multi-modal magnetic resonance imaging (MRI) with immunohistochemical studies and neurobehavioral studies. The multi-modal MRI studies include high resolution anatomical, diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), perfusion imaging, and dynamic contrast enhanced MRI (DCE MRI). DTI and MTI will be used to probe the integrity of fiber tracts while DCE MRI and perfusion MRI will allow us to identify and characterize the neovasculature, determine the vascular density, and map the blood-spinal cord permeability. Sophisticated image processing techniques will be implemented for generating and displaying the neovasculature. The temporal changes in the endogenous VEGF expression and its correlation with angiogenic activity following SCI will be investigated for interpreting the MRI results on a rational basis. Detailed immunohistochemical studies will be performed for identifying neovasculature. The MRI measures will be correlated with neurobehavioral scores If the role of angiogenesis in recovery from SCI is confirmed, it should be possible to treat SCI subjects with drugs that manipulate the angiogenic activity to augment the endogenous repair processes. In addition, it is possible to modulate angiogenesis in conjunction with other treatments, such as cellular grafts to further enhance the recovery from SCI. Thus the proposed studies have a very high degree of clinical relevance. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic central nervous system disease that affects 2.5 million patients worldwide. Currently, there is no cure for MS, but a number of disease modifying drugs have been either approved by the FDA or undergoing clinical trials. MS has a complex clinical course that includes unpredictable relapses and variable remissions. This makes clinical evaluation of MS difficult. The most commonly used clinical instruments for assessing the clinical status are limited in their sensitivity and can not detect subclinical activity. Thus, there is a need for identifying a surrogate that provides an objective and reproducible measure of the disease state. Magnetic resonance imaging (MRI) is the most sensitive imaging modality for noninvasively investigating MS. It is possible to derive a number of metrics that are based on multi-model MRI measurements that reflect different pathological aspects of MS. However, the correlation between the clinical status and various MRI-derived metrics is, at best, modest. This is, at least, in part due to the fact that many of the correlative studies are based on a single or a combination of a few MRI metric. A combination of MRI metrics that include gray matter, white matter, and spinal cord is expected to result in better correlation with clinical measures. The main objective of this proposal is to identify a surrogate that combines information from various MRI measures that include both brain and spinal cord. These studies will also identify and quantify the so called "normal appearing tissue" in MS that is known to be pathological and thought to represent microscopic or diffuse pathology in MS. In order to realize the main objective of this proposal, we will develop, implement, and evaluate a number of advanced MRI acquisition and analysis, and image processing techniques. We will determine the longitudinal changes in the MRI-derived metrics in a cohort of MS patients and identify an optimum combination of these metrics that correlate with clinical disability as assessed by the extended disability status score (EDSS) and MS functional score (MSFC). The proposed multi-model MRI and longitudinal studies along with clinical evaluation should help identify appropriate surrogate(s), based on multiple MRI-derived metrics. Relevance to Public Health: Identification of surrogate in MS should revolutionize MS clinical trials, expedite technology transfer in neuropharmaceuticals and literally save millions of dollars in clinical trial expenses. The system should also empower clinicians in general to customize management of individual patients based on well-founded sound principles of the use of more widely available quantitative MRI. While the main emphasis is on MS, this system should be readily adaptable to investigate and manage various neurological disorders that require accurate determination of tissue volumes and their temporal change. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Proton magnetic resonance spectroscopic imaging (MRSI) allows the in vivo determination regional distribution of various neurochemicals. The pathologic specificity and inherently quantitative information provided by MRSI should help understand the mechanisms involved in various neurological disorders and improve patient management. In spite of its demonstrated use, MRSI is not routinely used because of lack of fast and automatic MRSI analysis tools. In order to overcome these limitations and exploit the power of MRSI, this application proposes to develop a fast and automated software package for determining the absolute concentrations of brain metabolites that are observed on proton MRS. The proposed fast, robust, and automated analysis software package will be freely available to users. This software is based on artificial neural networks. It has been demonstrated to be fast and robust. In order to account for the contribution of multiple tissues to a given spectroscopic voxel, the software includes fast image segmentation technique and combines it with the MRSI analysis software. The fast segmentation technique is based on phase sensitive inversion recovery imaging sequence that allows the reconstruction of images in phase sensitive and magnitude modes that exhibit dramatically different tissue contrasts. For wider use by the neuroimaging community, this software will be developed on a PC platform and distributed. PUBLIC HEALTH RELEVANCE: This proposed application is in response to the RFA for the development of Neuroinformatic tools to serve the neuroimaging community. The proposed software would allow both neuroscientists and clinicians to analyze the proton MRSI data to determine how various neurological disorders affect the regional metabolic distribution in brain. This information would be important for gaining an insight into the disease processes and also serve as diagnostic tool for improved patient management.

Recent diffusion tensor imaging (DTI) studies fnsm our laboratory and others have demonstrated significantly reduced fractional anisotropy (FA) in the corpus callosum in cocaine-dependent subjects relative to controls. The changes in FA have been interpreted as an indication of altered myelin. The specific underlying neuropathology of these white matter changes and if these pathological changes can be altered by cocaine abstinence or novel phramacotherapy, however, remain to be determined. Understanding the pathological changes between nornial, healthy individuals and cocaine-addicts is not simple because of difficulties in creating a completely controlled environment. In addition, histologic confirmation of the proposed pathologic mechanism is difficult to realize in humans. In the proposed translational studies, using multi-modal magnetic resonance imaging and end point histology in rodents treated with chronic cocaine, we will determine the effects of 1) dose of cocaine and method of administration on a) regional brain atrophy measured on high resolution structural MRI with tensor based morphometry, b) white matter pathology as measured by DTI and magnetization transfer ratio, c) regional cerebral blood flow as determined by MRI-based arterial spin labeling, and d) metabolite concentrations as determined by proton magnetic resonance spectn^scopy and 2) administration of the novel adenosine A2A receptor antagonist SYN115 on cocaine associated white matter pathology, regional brain volumes and regional cerebral blood flow. These multi-modal studies in rodents should help characterize neuropathological changes and institute rational-based treatments in human cocaine abusers.

DESCRIPTION (provided by applicant): The relation between inflammatory lesions and atrophy (global, tissue-specific, and regional) that is thought to represent neurodegeneration in multiple sclerosis (MS) is of fundamental importance in understanding the pathogenesis of this disease. We hypothesize that the activity and spatial location of the lesions drive the subsequent atrophy in MS. This hypothesis will be verified by analyzing the MRI data acquired on the CombiRx cohort. CombiRx is a multi-center, double blinded clinical trial with 1008 enrolled patients. Patients are being followed over a minimum period of 3 years with all patients followed until the last patient completes in January 2012 allowing for up to 6.5 years of follow up on some patients. MRI data on this cohort is acquired with a rigorous MRI protocol and the treatment assignments have remained constant. The five specific aims of this proposal are: 1) automatic identification of T2-hyperintense, T1- hypointense, and Gd enhancing lesions and their spatial location, 2) determine the cortical thinning that is a measure of cortical pathology,3) assess the pathology in the normal appearing brain tissue based on the T2 values, determined on a voxel-by voxel basis using the dual echo images, 4) determine the whole brain, tissue specific, and regional atrophy, and 5) determine the effect of lesion activity and their spatial location on the regional atrophy and examine the role of MRI measures as possible biomarkers/predictors of the disease. The image segmentation will be performed using the multi- spectral segmentation in combination with the atlas-based techniques. Activity of both T2-hyperintense and T1- hypointense lesions will be determined by subtracting images acquired at different time points following diffeomorphic nonlinear image registration. Regional atrophy will be determined using the tensor based morphometry. The effect of connectivity between the lesion location and regional atrophy will be investigated using the white matter atlas. Finally composite MRI measures will be correlated with both EDSS (extended disability status scale) and MSFC (MS functional scale) and their individual components. This strategy that includes spatial information should allow identification of robust biomarkers/predictors of the disease. The analysis based on a large and clinically well characterized cohort followed over a relatively long period of time to understand the relationship between inflammation and neurodegeneration is a unique feature of this proposal. Abbreviations: CNS (central nervous system); DGM (deep gray matter structures); DIR (double inversion recovery); DSI (Dice similarity index); DTI (diffusion tensor imaging); EDSS (extended disability status scale); FoE (field of expert); GM (gray matter); ICBM (international consortium for brain mapping); MNI (Montreal Neurologic Institute); MRF (Markov random field); MRI (magnetic resonance imaging); MRIAP (MRI Automated Processing); MRS (magnetic resonance spectroscopy); MS (multiple sclerosis); MSFC (MS functional composite); MTR (magnetization transfer ratio); NABT (normal appearing brain tissue); NAWM (normal appearing white matter); PD (proton density); RGM (regional GM); RRMS (relapsing remitting MS); RWM (regional white matter); SIENAX (Structural Image Evaluation, including Normalization, of Atrophy (X-sectional); SPM (statistical parametric mapping); TBM (tensor based morphometry); TOADS (Topology preserving Anatomical Segmentation); VBM (voxel based morphometry); WM (white matter)

Description: Identification of active lesions is critical for the management of multiple sclerosis (MS) patients. Currently this identification is based on post-contrast T1-weighted magnetic resonance imaging (MRI). However, there are safety concerns with repeated administration of gadolinium ?based contrast agents (GBCAs). Thus, there is critical need for identifying active lesions without the use of GBCA. In this application we propose to identify the active lesions without administering GBCA using texture analysis (TA) using multi- modal non-contrast MRI and support vector machine (SVM) learning. A unique feature of this proposal is that the results will be analyzed using MRI data acquired on a large cohort of MS patients (~1000) as a part of phase III, randomized, double-blinded clinical trial (CombiRx). In addition texture features will be identified that can predict lesions that convert into tissue destructive lesions, so called black holes. This has important clinical implications since there is correlative evidence that balk holes are associated with clinical disability. A novelty of this project lies in performing texture analysis in real time that allows the physician to make the decision about administering GBCA on the spot while the patient is still in the scanner. This greatly helps in eliminating and/or minimizing the number of times GBCA needs to be administered. For real time analysis, the necessary infrastructure that includes automatic processing pipeline and integration of the MRI scanner with high performance computational resources located at Texas Advanced Computing Center (TACC) in Austin. Finally to establish real time TA as a viable alternative to GBCA administration for identifying active lesions, the developed methods will be prospectively applied to MS patients undergoing MRI scans as a part of routine clinical management.