The overall long-term goal of the Center for Magnetic Resonance and Optical Imaging (CMROI) is to develop cutting edge core Magnetic Resonance and Optical imaging technologies in support of the biomedical research community at the University of Pennsylvania and other institutions across the country to address clinical problems and to further the fundamental understanding of biophysical, physiological, structural, and functional properties of biological systems. Based on the driving biomedical projects identified by our collaborators, we developed the following four broad areas of Technological Research and Development (TR&D): The first TR&D project deals with the development of novel rotating frame MRI techniques for studying the structural, biochemical and metabolic aspects of cartilage, brain, and tumors, with direct application to Arthritis, Alzheimer's Disease and cancer. The second TR&D focuses on the development of quantitative perfusion MRI at ultra high field {7T} scanners, real time fMRI as well as methods for integrating perfusion MRI with optical imaging for the study of stroke and neurodegeneration. The 3rd TR&D develops novel image reconstruction strategies to overcome artifacts due to motion and to quantify the rapid dynamics of contrast agents in cancer and to acquire dynamic hyperpolarized gas MRI of the lungs. The final TR&D develops multi-modal state-of-the-art instrumentation combining optical imaging and MRI, and develops diffuse correlation spectroscopy (DCS) for blood flow monitoring/imaging of diseased tissues in stroke and breast cancer. The Resource emphasizes clinical translation of its TR&D work and actively collaborates on ongoing research projects. It provides service in the use of state-of-the-art MRI including a whole-body 7T research MRI scanner, optical imaging and hyperpolarized gas imaging systems, and software resources developed by the Resource. The Resource also maintains an extensive training and dissemination program in biomedical imaging and a dedicated wiki-based website. The Resource within the auspices of the Radiology Department at the University of Pennsylvania remains committed to intellectual interchange and the interdisciplinary pursuit of basic and clinical medicine.

Public Health Relevance

Imaging technologies developed by the resource will have substantial impact on fundamental understanding, early diagnosis, and development of novel therapies for several diseases including Alzheimer's disease, Arthritis, Cancer, Stroke, and chronic obstructive pulmonary disease (COPD). OVERALL CRITIQUE: This Research Resource has been underway since 1984 at the University of Pennsylvania. The current 5 year renewal continues with the overall focus of development of technology for advanced magnetic resonance human imaging and technology for optical imaging techniques appropriate for studies of human diseases. The resource called Center for Magnetic Resonance and Optical Imaging has focused on pursuing the development of magnetic resonance and optical imaging methodologies and plans to continue pursuing this mission with emphasis on translation to clinical applications. Over the last 25 years a number of seminal papers (from a total of ~ 1200), as well as patents, hardware and software (e.g. pulse sequences) have been developed and these have been and continue to be disseminated to large and small clinical programs as well as to other major research entities. The PI and the scientists associated with this resource continue to be leaders in developing state of the art technology for non-invasive imaging, applied to a diverse set of diseases. The founding PI, Dr. Jack Leigh, died in 2007 and his long-time colleague, Dr. Ravinder Reddy is now the RR director. The resource is a unit in the Dept. of Radiology at Univ. of Pennsylvania, and also enjoys participation from the CAMRIS (Center for Advanced Magnetic Resonance Imaging and Spectroscopy) and is now a key element of the University of Pennsylvania's Institute for Translational Medicine and Therapeutics that is the home for a CTSA now in its 3 rd year. Progress includes 186 peer-reviewed journal articles that include work of the RR scientists and work of collaborators, 13 patents and NIH grant awards in each of the 4 project areas. Overall the committee concluded this RR has made significant progress and the technical plans for the future are excellent. The four technical research and development projects as well as the other elements of a Research Resource are critiqued below. 1) Rotating Frame Imaging Techniques. This project has evolved over the past two review periods with a main focus on introduction of a new method of MRI imaging that is sensitive to macromolecular content of tissues, thus able to image changes in cartilage and intervertebral disc spaces. The major innovation during the past period is demonstration of imaging at fields of 3T and 7T where major physical barriers had to be overcome. Success in reducing the time to gather data and success in achieving results on human subjects within FDA guidelines for absorbed power are evidence of major progress in this project. There is a need for studies of the biophysical mechanisms that underlie the contrast seen by the spin-lock MRI and the committee was assured that this would receive priority. This project showed evidence that other organs such as heart and liver would be studied as the arthritis clinical work is transferred to clinics as indeed it is. 2) The Functional MRI project uses the MRI method of arterial spin labeling to measure brain and breast blood flow. This method was developed at the RR and is now being transferred to the community as a pulse sequence protocol by Siemens and General Electric as part of their Magnetic Resonance instruments. The plan to go to higher field, plans for studies in children with compromised brain blood flow as well as plans to introduce the method into the evaluation of stroke patients and arteriovenous malformation patients were seen as excellent translational applications. The collaboration with Project 4 that uses optical methods was considered important but needed more specifics. 3) Dynamic Radial MRI is a MRI physics project to achieve rapid imaging in motion fields. The basic technique is to sample in radial directions in frequency space rather in a rectilinear fashion so as to acquire data rapidly and allow dynamic imaging as well as minimize motion artifacts. The dynamic imaging is needed to image the temporal changes in contrast after injection of contrast material. A subproject emphasizes pulmonary function imaging using the noble gas helium whose properties allow imaging of air spaces in the lungs. The connection between the dynamic radial imaging and the pulmonary project is that the latter needs the former's technology. There was general enthusiasm regarding these two projects, and an expectation that the investigators will continue to mature under the mentorship of Dr. Mitchell Schnall. 4) Optical Imaging is a new project that has been underway for the past few years under the leadership of Dr. A Yodh. This project grew out of the long-term interest and innovations of Dr. Brittan Chance and Dr. John Schotland. One part of the project is an instrumentation intensive development for improving diagnosis and monitoring of breast tumors. The objectives include combining optical imaging with MRI and development of diffuse correlation spectroscopy. The new leadership supported by very strong collaborators is seen as a very strong element of this RR. The other direction is to develop a simple hand-held probe for tissue monitoring with an immediate application to the brain for blood flow monitoring. The committee concluded this was an excellent project. Driving Biomedical Projects: The eleven DBPs are strongly related to their respective core technology programs and overall they were evaluated as excellent though not all had compelling arguments for informing the technical projects in the future. Two of these projects have engaged PIs from other institutions and this was seen as a positive. Collaboration and Service Projects: There are 20 listed collaboration projects of which only 3 are outside the UPenn. The 9 service projects also were only within the institution. Though the projects were relevant and do represent a breadth of applications of the RR technology, the committee concluded the leadership needed to improve the efforts to engage collaborations outside the Univ. of Pennsylvania if this is to continue as a National Resource. Training: A large number of students and post-doctoral researchers have been trained by the RR. The success of the RR trained individuals over the years is outstanding. However, there was a paucity of information regarding the plans for training in the future in the written proposal though some information was forthcoming at the site visit. The committee was very impressed by the 41 posters and the quality of students involved in the work of this RR. The connection of their work to the RR projects was exceptional. Overall, in spite of the great record of graduates from the Jack Leigh/Brit Chance mentorship, the formal training program was not as strong as it needs to be in the future. Dissemination: The dissemination of information has gone beyond claims for number of papers, patents, and appearances at meeting because a very innovative Internet presence has been established and the dissemination component of this RR is now considered outstanding. Resources: To the already large array of imaging resources has been added a 7 T whole body magnet with remarkable institutional support to a separate shared instrument grant. With the addition of this resource to the established working magnetic resonance and optics instrumentation, the RR is probably the richest physical resource institution in America. Administration: Factors such as external advisory board, communications, and annual reports were considered satisfactory by the committee. The administrator is very experienced and there is a high level of mutual respect between the investigators and the administrator. However the committee noted a number of weaknesses in the administration of the RR that is evidenced by the variable quality of the application, the spotty discipline in some presentations and the missing details regarding how resources are allocated. TECHNOLOGICAL RESEARCH AND DEVELOPMENT: TR&D 1: Rotating Frame Imaging Methods Investigators: Walter R. T. Witschey, Arijitt Borthakur and Ravinder Reddy Priority Score: 2.4 DESCRIPTION (provided by the applicant): The purpose of this project is to develop T1? MRI techniques as a means for early disease detection and to validate models for T1? relaxation in biological tissues. Early detection of molecular disease is critical for preventing disease progression and reversing the course of the disease when the cost of treatment is low and treatment success rate is much higher. This project focuses on the early detection of molecular changes in pathologies such as arthritis, intervertebral degenerative disc disease (DDD), Alzheimer's disease (AD), and cancer by T1? MRI. We have previously shown that proton T1? mapping enables the quantification of early biochemical changes in articular cartilage and intervertebral discs. In both these disease models, T1? correlates strongly with the proteoglycan content of the tissue. Subsequently, T1? relaxation mapping studies have been performed on both asymptomatic and symptomatic human subjects and in animal models. In addition, we have been encouraged by recent studies showing increased T1? in AD patients'brain compared to age-matched controls'brain. Recently, groups utilizing the technique are coming to the realization that there are several fundamental limitations in the current imaging paradigm that restrict the achievable resolution and SNR within a reasonable scan period. Briefly, the current implementation is sub-optimal because T1? contrast is lost during repeated excitation and relaxation that occur during the, otherwise, time-efficient multi-echo acquisition strategy. Additionally, inefficient lipid suppression and high radiofrequency (RF) power deposition issues also need to be addressed. To fulfill these requirements, the current project proposes to develop a new T1? MRI pulse sequence by expanding upon the developments and progress made in the previous funding period. In addition to reducing RF power and increasing time efficiency of T1? MRI, the new method opens avenues for research into molecular motions over a large frequency range in vivo. The potential exists for studies at ultra high fields (7T and higher) with built-in lipid suppression and generating dispersion-weighted contrast in many types of tissues. The new pulse sequence strategy may also play a role as an optimal readout sequence for other applications such as fMRI and arterial spin labeling (ASL) perfusion MRI in ultra high fields. Developments in the TR&D are driven by four driving biomedical projects and six collaborative and service projects from both within and outside the primary institution.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZRG1-SBIB-Q (40))
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Levy, Abraham
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Ban, H Y; Schweiger, M; Kavuri, V C et al. (2016) Heterodyne frequency-domain multispectral diffuse optical tomography of breast cancer in the parallel-plane transmission geometry. Med Phys 43:4383
Finkelstein, Joel S; Lee, Hang; Leder, Benjamin Z et al. (2016) Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J Clin Invest 126:1114-25
Xie, Long; Dolui, Sudipto; Das, Sandhitsu R et al. (2016) A brain stress test: Cerebral perfusion during memory encoding in mild cognitive impairment. Neuroimage Clin 11:388-97
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McCarthy, Ann L; Winters, Madeline E; Busch, David R et al. (2015) Scoring system for periventricular leukomalacia in infants with congenital heart disease. Pediatr Res 78:304-9
Sharma, Anup; Newberg, Andrew B (2015) Mind-Body Practices and the Adolescent Brain: Clinical Neuroimaging Studies. Adolesc Psychiatry (Hilversum) 5:116-124
Samartzis, Dino; Borthakur, Ari; Belfer, Inna et al. (2015) Novel diagnostic and prognostic methods for disc degeneration and low back pain. Spine J 15:1919-32
Singh, Anup; Reddy, Damodar; Haris, Mohammad et al. (2015) T1ρ MRI of healthy and fibrotic human livers at 1.5 T. J Transl Med 13:292
Haris, Mohammad; Yadav, Santosh K; Rizwan, Arshi et al. (2015) T1rho MRI and CSF biomarkers in diagnosis of Alzheimer's disease. Neuroimage Clin 7:598-604
Franklin, Teresa R; Jagannathan, Kanchana; Wetherill, Reagan R et al. (2015) Influence of menstrual cycle phase on neural and craving responses to appetitive smoking cues in naturally cycling females. Nicotine Tob Res 17:390-7

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