John A. Detre - US grants

Stroke is a leading cause of morbidity and mortality in the United States and throughout the world. The purpose of the proposed research project is to characterize in vivo brain parenchymal changes in a rat model of focal stroke with reperfusion using magnetic resonance (MR) techniques. Functional assessment of the ischemic region will be carried out using a novel technique for noninvasive quantitative MR imaging of tissue perfusion, which will be used to acquire time-resolved perfusion images following acute focal stroke and subsequent reperfusion. Further characterization will be carried out using various other types of MR imaging methods which yield complementary types of tissue contrast, and comparison will be made using histopathologic analysis in the chronic stage as a "gold standard' of brain infarction and recovery. These techniques will be used to determine the MR correlates of the "ischemic penumbra", namely the regions of potentially reversible ischemia injury. Once the MR correlates are determined, the effects of various therapies aimed at reducing tissue damage in brain ischemia can be readily tested using this model. Because MR techniques are noninvasive, this approach is immediately applicable to the investigation and therapy of acute stroke in humans. For example, the accurate determination of potentially salvageable brain tissue in a patient with acute stroke would improve the risk-benefit ratio for thrombolytic therapy or other therapies which carry significant risks. To this end, technical development of the MR perfusion technique for use in humans will take place simultaneously with the rat studies.

bioimaging /biomedical imaging; brain injury

DESCRIPTION: (Applicant's abstract) Epilepsy is among the most common neurological disorders, affecting approximately one percent of the adult population. Although anticonvulsants provide reasonable control of seizures in the majority of affected patients, up to twenty percent are refractory to medical therapy. In patients with refractory temporal lobe epilepsy (TLE), temporal lobectomy is beneficial, resulting in better seizure control, better integration into society, and a lower incidence of unexplained death, but carries a risk of producing memory or language disturbances. Assessment of memory function is a critical aspect of the preoperative evaluation for temporal lobectomy. Functional magnetic resonance imaging (fMRI) techniques allow task-specific regional brain function to be visualized noninvasively with high spatial resolution, and should be applicable to the preoperative assessment of abnormalities in memory function. Preliminary data obtained from normal volunteers and patients with TLE demonstrate that fMRI can noninvasively determine hemispheric asymmetries in the recruitment of mesial temporal lobe (mTL) structures during the performance of episodic memory tasks. In contrast to normal subjects who show symmetrical mTL activation, patients with TLE show significant asymmetries. The lateralization of the measured asymmetries are in agreement with findings by invasive testing using intracarotid amobarbital, currently the "gold-standard" for the preoperative assessment of memory and language laterality. The proposed research will use fMRI during memory tasks to delineate mTL brain regions involved in episodic memory function, and will validate a role of fMRI as a clinically useful tool in the presurgical evaluation of patients with medically intractable temporal lobe epilepsy. We will assess its clinical value by prospectively comparing the results of fMRI memory assessment with intracarotid amobarbital testing (IAT) as well as post-surgical neuropsychological outcomes in 125 patients with TLE who undergo temporal lobectomy. The results of fMRI will also be compared with volumetric assessment of mTL structures to examine the correlation between structural changes and functional deficits in mTL structures. Validation of an fMRI protocol for assessing memory function will improve the safety and quality of the preoperative assessment for temporal lobectomy, and may have important implications for neurosurgical planning and prognosis.

DESCRIPTION: (Adapted from the Investigator's Abstract) A fundamental aspect of brain physiology is the coupling between regional neuronal activation and changes in regional cerebral blood flow (CBF), herein referred to as activation-flow coupling (AFC). This coupling is the basis of many functional neuroimaging techniques that detect regional brain activation in response to specific sensorimotor or cognitive tasks by utilizing changes in regional CBF as a surrogate marker for neuronal activation. However, neither the specific mechanisms underlying AFC nor the effects of pathophysiological changes or the influences of vasoactive drugs on AFC have been well characterized. Neuroimaging techniques such as functional MRI (fMRI) can monitor changes in regional hemodynamics with high spatial and temporal resolution. Activation paradigms may be administered singly, periodically, or in blocks, yet the hemodynamic consequences of these differing experimental designs are largely unknown. Further, as neuroimaging studies are extended to patient populations for diagnostic purposes, the effects of pathophysiological changes on AFC responses must be better understood to allow results of such studies to be correctly interpreted. The proposed research is motivated by the goal of better understanding factors influencing AFC responses and neuroimaging techniques which rely on AFC as a surrogate marker of neural activity. Signal averaged laser Doppler monitoring will be used to measure AFC responses in a rat model of AFC, with CBF changes recorded from somatosensory cortex in response to electrical forepaw stimulation. The applicant will also monitor tissue oxygenation changes by in vivo phosphorescence quenching to characterize changes in oxygen utilization in relation to blood flow and will monitor somatosensory evoked responses elicited by stimulation as a measure of neural activity. A laser Doppler-imaging system will also be implemented to investigate spatial aspects of AFC. These studies will provide further insight into the parameters affecting the AFC. A computerized 'virtual instrument' allows stimulus and recording parameters to be flexibly controlled. Specific aims of the proposed research include characterization of the stimulus timing effects on the AFC response, characterizing oxygenation changes; characterizing the interactions between AFC and vasomotion oscillations; and the effects of hemodynamic impairment on the AFC response. These studies will provide further insight into the parameters affecting the AFC response, and will suggest approaches for optimizing and interpreting functional imaging data.

Because of the close coupling between regional neural activity and changes in regional cerebral blood flow (CBF), imaging methods capable of measuring changes in CBF may be used to visualize changes in regional brain activity. Functional magnetic resonance imaging (fMRI) methods have emerged as the preeminent method for visualizing the neural correlates of cognition. Imaging methods are typically the sole means of directly assessing human brain function and provide an important link between behavior and brain that complements observations made in individuals with brain lesions, providing converging evidence of functional localization and organization. Most fMRI studies have utilized blood oxygenation level dependent (BOLD) contrast, which reflects a complex interaction between changes in blood flow, blood volume, and other biophysical parameters. While BOLD fMRI contrast is relatively easy to obtain, BOLD fMRI is only reliable for measuring relative changes in signal intensity over a few minutes or less, and BOLD fMRI signal changes are difficult to detect in regions of high static susceptibility. An alternative approach to visualizing regional brain activity with fMRI is to measure CBF changes directly using magnetic arterial spin labeling (ASL) as a noninvasive and nominally diffusible flow tracer. ASL perfusion MRI allows absolute CBF to be quantified both at rest and with task activation, and is stable over prolonged periods. Furthermore, the effects of ASL can be sampled using any imaging sequence, allowing perfusion to be measured in regions of high static susceptibility gradients. This approach is particularly suitable for imaging a broad range of cognitive processes that may affect resting brain function, occur gradually, or involve brain regions affected by susceptibility artifacts. With funding from the National Science Foundation to Dr. John A. Detre, this project will continue the development and application of high field ASL perfusion fMRI for specific use in cognitive neuroscience. Previous work from the PI's laboratory has demonstrated the feasibility of using ASL perfusion fMRI to measure brain function at rest or with sensorimotor task activation in the presence of artificially created susceptibility gradients and over prolonged durations. More recently, the benefits of high magnetic field strength for increasing the sensitivity of ASL perfusion fMRI and its applications to more subtle activation during cognitive paradigms have been demonstrated. Technical development during this project will focus on improving sensitivity, spatial resolution, and temporal resolution of ASL perfusion fMRI through the use of high field, optimized 3-dimensional imaging, multicoil arrays, parallel imaging, background suppression, and minimization of physiological noise. Validation of improved ASL perfusion fMRI for cognitive neuroscience will focus on subtle cognitive activation in orbitofrontal cortex (OFC) during risk and reward assessment that is challenging to detect with BOLD fMRI, and will directly compare brain activation obtained using ASL and BOLD fMRI.

There are many potential impacts of this research. The work will broaden applications of fMRI by providing an alternative to BOLD imaging. Advances in perfusion imaging will be disseminated to other research sites by the multidisciplinary research team.

DESCRIPTION (provided by applicant): Treatment for stimulant addiction is often complicated by relapse. Behavioral factors contributing to relapse include cue-induced drug craving and an inability to weigh the long-term consequences of a choice. These states have been linked, respectively, to limbic activation and to defects in ventral orbitofrontal brain function. Functional brain imaging provides a noninvasive means of studying alterations in regional brain function accompanying behavioral states in humans, and the advent of functional magnetic resonance imaging (fMRI) has greatly increased it's accessibility. While the majority of fMRI studies have used blood oxygenation level dependent (BOLD) contrast as a marker for regional neural activation, this approach also has shortcomings, including lack of absolute quantification, baseline drift with poor sensitivity for very low frequency events, and signal loss in certain brain regions such as the ventral orbitofrontal cortex due to static susceptibility effects. Over the past decade, we have been developing methods for direct measurement of cerebral blood flow (CBF) using MRI. This class of techniques, termed arterial spin labeled (ASL) perfusion MRI, utilizes magnetically labeled arterial blood water as an endogenous tracer. Our preliminary data demonstrate that: 1) CBF values measured using ASL perfusion MRI are reproducible, 2) task-activation measured by ASL shows less intersubject variability than BOLD, 3) ASL contrast shows noise characteristics that make it suitable for studying sequential changes in resting or activated brain function over long periods, and 4) signal changes detected by ASL can be measured in the presence of large static susceptibility gradients. We propose to further develop and validate ASL perfusion MRI methods for the purpose of enhancing our investigations into the neurobiology of cocaine addiction. Specifically, we will improve the measurement of CBF in regions of high static susceptibility (e.g, the amygdala and ventral frontal lobes), implement ASL perfusion MRI at high field, and validate the use of ASL for examining CBF under resting and activated conditions in cocaine patients and contrcontrols. The anticipated findings of limbic activation during cue-induced craving, resting limbic hypoperfusion, and ventral orbitofrontal perfusion deflects may reflect core vulnerabilites for relapse and will provide direct evidence for the advantages of ASL perfusion in the study of addiction-related states.

DESCRIPTION (provided by applicant): The Neuroscience Neuroimaging Center (NNC) NINDS PSO Institutional Center Core was established in 2003 to provide researchers at the University of Pennsylvania and later collaborating institutions with access to multidisciplinary expertise in neuroimaging research. This NINDS PSO Center Core consolidates a broad range of methodological expertise in neuroimaging to create a community of investigators focused on the application of advanced neuroimaging methods to neuroscience research who work together to optimize resource utilization and provide users with access to the latest methodologies for image acquisition and analysis. This centralization of methodological expertise has improved the quality and scope of neuroimaging methodologies available, and has reduced the cost of individual grant proposals, which would otherwise need to include much or all of their required expertise within their specific project budgets. An Administrative Core provides oversight for the Center, administrative support for its resources, regulatory support for its users, and is guided by a Steering Committee comprised of Core Directors, consortium representatives, and user representatives. An Acquisition Core provides technical support for magnetic resonance and optical imaging protocol development and implementation, imaging quality assurance, and for implementing capabilities for stimulus delivery and biobehavioral response monitoring. An Analysis Core supports structural morphometry, diffusion tensor tractography, localized and global brain segmentation, image visualization, statistical modeling, and genomic analyses by providing both general tools and customized data processing pipelines. An Informatics Core maintains a state-of-the-art data processing environment with access to a broad range of image analysis software, data storage and archiving, and system administration support for both core computing and users. A consortium consisting of the University of Pennsylvania (Penn), Children's Hospital of Philadelphia (CHOP), and the Moss Rehabilitation Research Institute (MRRI) in Philadelphia with the NNC currently includes 15 investigators with qualifying NINDS grants along with numerous other basic and clinical neuroscientists working within the NINDS mission who use the Core.

ABSTRACT NOT AVAILABLE

DESCRIPTION (provided by applicant): The applicant is a mid-career clinician-scientist whose research focuses on applications of functional neuroimaging in basic and clinical neuroscience. Because neuroimaging methods are noninvasive, they are particularly well suited to patient-oriented research. Neuroimaging methods can be used to elucidate the pathogenesis of neurological disorders, aid in differential diagnosis, and serve as surrogate biomarkers for monitoring disease progression and assessing therapeutic efficacy. The applicant is widely recognized for the development and validation of magnetic resonance imaging (MRI) methods for quantifying cerebral blood flow, for clinical applications of functional MRI (fMRI), particularly in epilepsy, and for basic studies in functional brain physiology using both MRI and optical methods. Patient-oriented research for the proposed career development award will additionally assess the utility of optical cerebral blood flow monitoring in the hospital management of acute stroke, and evaluate the efficacy of functional stimulation as a means of augmenting cerebral blood flow in the peri-infarct region. In addition to pursuing his own research program, the applicant also devotes a considerable effort to institutional programmatic development in neuroimaging, and to mentoring junior faculty and other trainees. He founded the Center for Functional Neuroimaging, which provides multidisciplinary infrastructure support for neuroimaging research, and is of particular value to junior faculty who lack the extensive resources required to initiate new neuroimaging projects. The Center for Functional Neuroimaging currently receives major support from an NINDS P30 Center Core (NS045839). The applicant also mentors several junior faculty members from clinical and basic science backgrounds in translational neuroimaging research, and is pursuing a training grant in interdisciplinary neuroimaging that will include multidisciplinary training and patient-oriented research for both basic science and clinical trainees. As part of this overall training effort, the applicant has proposed to develop an interactive seminar in translational neuroimaging that will cover major domains of brain function and disorders using a systems-oriented approach. Through the proposed K24 mid-career development award, the applicant seeks 25% effort for individual and group mentoring of trainees, particularly junior clinician-scientists, for new patient-oriented research (POR) projects using neuroimaging in stroke management, and to expand his own knowledge of important emerging areas in neuroimaging including spatiotemporal statistics, use of imaging in clinical trials, and molecular neuroimaging.

DESCRIPTION (provided by applicant): Changes in cerebral blood flow (CBF) reflect changes in regional brain function and provide the physiological basis for most functional brain imaging. Magnetic resonance imaging (MRI) is currently the most versatile tool for brain imaging, and provides detailed information about both structure and function within the same modality. Arterial spin labeled (ASL) perfusion MRI uses magnetically labeled endogenous arterial blood as a quantitative flow tracer to measure CBF noninvasively using standard MRI hardware. Over a decade of research in human applications of ASL perfusion MRI in our laboratories and elsewhere have demonstrated that clinically significant changes in regional CBF can be detected in a broad range of neurological and psychiatric disorders including stroke, epilepsy, degenerative diseases, addiction, and mood disorders as well as with functional activation using sensorimotor or cognitive tasks. ASL has been shown to provide comparable CBF values and test-retest stability to other modalities, but is uniquely acquired completely noninvasively and concurrently with structural MRI. While BOLD contrast is currently the most widely used approach for functional MRI (fMRI) during task activation, BOLD reflects a complex and incompletely characterized interaction between biophysical and physiological processes with minimal capability of assessing resting brain function. Assessment of resting brain function is critical for clinical studies involving pharmacological interventions or pathophysiological changes, and for characterizing functional brain phenotypes. ASL perfusion MRI can noninvasively quantify CBF both at rest and with task activation. Furthermore, because ASL perfusion MRI measures a purely biological parameter (blood flow in ml/g/min), it provides a stable and reproducible measure of regional brain function that is independent of scanner effects, and therefore suitable for multisite or longitudinal studies where scanner platforms may vary. Numerous methodological enhancements now provide much higher quality ASL perfusion MRI data than was previously available. However, access to cutting-edge ASL methodology is currently limited to a few labs with specific expertise in ASL implementation. This project will implement and validate state-of-the-art ASL pulse sequences for the two most common scanner platforms, GE and Siemens, which comprise the majority of deployed scanners. The resulting sequences will capitalize on several recent methodological developments including high field strength, multicoil receiver arrays, parallel imaging, background suppression, T2*- insensitive imaging, and improved labeling schemes. Key parameters affecting quantification of CBF using ASL will also be assessed, and software tools for quality assurance and quantification of ASL perfusion MRI will be developed. The resulting pulse sequences and software will be made available to the research community as research products. Once the key acquisition and analysis parameters are defined, these approaches should also be readily adapted to other hardware platforms.Imaging provides new insights into human brain structure and function and is critical for further understanding brain disorders and their treatment. This project will develop software for obtaining and quantifying human brain function noninvasively using magnetic resonance imaging (MRI). The resulting technology will be made available to the biomedical community as a research product.

DESCRIPTION (provided by applicant): Imaging methodologies contribute to the elucidation of brain function in health and disease and there has been an exponential growth in the utilization of neuroimaging in brain research, yet few investigators possess the entire range of skills needed to carry our successful neuroimaging research. We propose the development of an interdisciplinary training program in "neuroimaging", a discipline combining an understanding of central nervous system organization and function, the biophysical basis for the various imaging methodologies used to assess brain function in vivo, and a familiarity with existing and potential clinical applications of imaging methods to neuropsychiatric disorders. Two pre-doctoral trainees and four postdoctoral trainees from basic science and clinical backgrounds will pursue a curriculum in neuroimaging methods and applications, participate in several seminar series pertaining to neuroimaging, and carry out research under the guidance of primary and secondary mentors with complementary expertise in neuroimaging methods and applications in basic and clinical neuroscience. A special interactive seminar series on "translational neuroimaging" will be organized and led by the program director specifically for the trainees of this program. The proposed program will share administrative support with and benefit from infrastructure support provided by the Neuroscience Neuroimaging Center NINDS P30 Center Core, which provides access to multidisciplinary expertise in image acquisition, image analysis, and image computing. A core faculty of investigators with active research in clinical neuroimaging and a track record of successful interdisciplinary research and training in this area will serve as preceptors for the proposed training program. Graduates of this training program will have received training in a broad range of topics including brain organization, function, and disorders, biophysics of imaging modalities, statistical analysis of multimodal imaging data and computational approaches, and will be prepared to develop and lead multidisciplinary research efforts utilizing neuroimaging methods to elucidate the pathogenesis of neurological and psychiatric disorders, to aid in differential diagnosis, and as a surrogate biomarker for monitoring disease progression and assessing therapeutic efficacy.

2. A Data Acquisition Core (formerly the MRI Acquisition Core) provides technical support for magnetic resonance and optical imaging protocol development and implementation, imaging quality assurance, and for implementing approaches for ancillary methods such as physiological monitoring and gating, neuropsychological task design, and behavioral response monitoring.

CRISP; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Physiologic pulse; Pulse; Pulse taking; Research; Research Personnel; Research Resources; Researchers; Resources; Site; Source; Spin Labels; Technology; United States National Institutes of Health

Core Services: The image analysis core provides consultation on the practical aspects of carrying out analyses of brain imaging studies, including the routine use of computer workstations in data management and statistical analysis as well as the operation of specific software packages. This includes one-on-one tutorials in the use of particular software packages for new users. The image analysis facility also provides group tutorial sessions on the use of new software packages, modules, or features, including the locally developed VoxBo package that provides unique capabilities for statistical modeling and parallel processing. Core personnel are familiar with a variety of widely used packages in image analysis, and are experienced in guiding new users requiring varying degrees of support through their analyses. The Data Analysis/Computing Core provides the computing infrastructure for users to carry out their analyses. In addition to efficiencies associated with centralizing computing support, the core also supports facilities that would be difficult for even senior investigators to assemble and support themselves. Building on our experience in supporting the computing needs of neuroimaging researchers during the previous funding period.

Area; CRISP; Computer Retrieval of Information on Scientific Projects Database; Educational workshop; Funding; Grant; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neurology; Pennsylvania; Research; Research Personnel; Research Resources; Researchers; Resources; Source; United States National Institutes of Health; Universities; Workshop

neuroimaging; Neurosciences; parent project;

DESCRIPTION (provided by applicant): This Research Training Program in Disease Oriented Neuroscience is designed to facilitate the transition between graduate training and a research-based career in neurology. R25 program trainees will receive career mentoring from experienced clinician scientists and basic researchers in Neurology along with research mentoring from clinical and laboratory research faculty in multiple departments and schools within the University of Pennsylvania. A focused educational program drawn from departmental as well as institutional programs will supplement laboratory research has been developed and refined over the prior project period, and includes training in translational research methods, applications, and the responsible conduct of research. The program is conducted in a large research-oriented institution with leading residency programs in adult and child neurology that trains some of the best candidates in the country. Between adult and child neurology, there are over 100 faculty members in our department, ranging from master clinicians, clinical educators, and clinical investigators to physician/scientists and basic scientists. Over 80% of graduating residents over the past 15 years have remained in academic medicine, and many have chosen careers as clinician scientists. The Hospital of the University of Pennsylvania and Children's Hospital of Philadelphia at the Perelman School of Medicine, where most of the clinical residency and fellowship training occurs, are located within a highly compact university campus in West Philadelphia spanning less than one half mile. Penn is also home to the first neuroscience institute in the country, the Mahoney Institute for Neurosciences, which consolidates over 150 faculty members from 32 departments and six schools pursuing neuroscience research at Penn. The range of research opportunities for our R25 trainees can thus be extended to the wider neuroscience community inside and outside the Department of Neurology through co-mentorship of trainees with a diverse array of eminent scientists carrying out research relevant to the NINDS mission to reduce the burden of neurological disease.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The P50 Center for Interdisciplinary Research on Nicotine Addiction (CIRNA) includes a highly interactive set of projects and cores focused on tobacco addiction and its treatment. Project 3 uses human neuroimaging to examine the neural substrates of early abstinence symptoms and medication response.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of this project is to develop and implement novel approaches for studying brain function that capitalize on the recent availability of a 7 Tesla whole body MRI system at the resource. In particular, arterial spin labeled (ASL) perfusion MRI should benefit from ultra-high field due to the dual benefits of increased sensitivity and longer T1 that together produce a theoretical 4-fold increase in ASL signal as compared to 3 Tesla. However, to realize this potential gain, TRD2 needs to develop strategies to address challenges in B0 and B1 inhomogeneity and SAR deposition. We also propose to use the increased sensitivity to BOLD contrast for real-time fMRI. Technical validation will be complemented by collaborative and service projects with applications in cerebrovascular disease, peripheral vascular disease, addictions, and brain mapping. The technology development and validation being carried out in TRD2 is driven by the need to accurately measure tissue perfusion, a critical biological parameter. Disorders of perfusion account for most of the medical morbidity mortality in the western world (MI, stroke, PVD) and perfusion is also a biomarker of regional tissue function in the brain and other organs. Accordingly, the activities of TRD2 are driven by the desire to measure a fundamental physiological function. This motivation is exemplified by 2 Driving Biomedical Projects that will benefit from TRD2 activities in ASL technology development for human CBF quantification both at 7T and at 3T, as well as from future efforts to implement ASL for animal models at 9.4T.

The Analysis Core integrates Penn's world-class research and development programs in neuroimaging data analysis to provide consultation and customization for experimental and statistical design, image processing and analysis, and data visualization and interpretation. In addition to advanced techniques and tools, that cover the range of data analysis and processing tasks relevant to statistical infer13nce in structural and functional imaging studies of the brain, many of which originated at Penn, the Core collaborates with the Informatics Core to establish robust neuroimage processing pipelines with minimal failure rate that scale to the cluster and cloud computing needed for large studies, and with the Acquisition Core to match analysis strategies to acquisition methods. Supported effort, leveraging the expertise and experience of Core investigators, allows services that specialize these standard workflows to improve detection power in novel study designs. These resources together with other stand-alone capabilities can be accessed either through local user installations or using Informatics Core facilities. In addition to individual consultation and training, dissemination to the general NNC community occurs through tutorials, seminars by Core personnel, institutionally sponsored workshops, and other programmed outreach activities that promote open science at Penn and beyond. In the next project period, the Core will continue its successful track record of linking with the Acquisition and Informatics Cores to drive development of, and transfer to NNC users, the next generation of methodological innovations in neuroimaging analysis.

Summary Recent advances in neuroimaging technique require powerful, multi-node computer clusters or cloud computing resources to perform parallel distributed processing. Development and operation of these computer resources draws upon specific expertise that is generally not available to individual NINDS investigators. The Informatics Core provides expert personnel to support NINDS users (and related projects) in the access and use of advanced computing resources. The Core's services include the maintenance of a virtual computing environment that integrates a rich suite of neuroimaging analysis software with system tools for distributed processing, software development, and statistical analysis. This environment will initially be deployed on an NNC-managed cluster with a combined 580 compute cores with over 1.5 TB of combined RAM, and over 1OOTB of storage, but towards the end of the project period (Year 4), it will be migrated to the Institution¿managed computing cloud. The Core will also deploy and maintain XNAT, a research imaging data archive capable of web-based management and processing of large imaging datasets. The Core offers a range of services that serve the NNC community as whole, as well as individual NINDS investigators. Community-wide services include hardware and software maintenance, interfacing of analysis pipelines with XNAT, mirroring of major reference imaging datasets in XNAT and education activities. Personalized services include customization of the NNC virtual environment, deployment if the environment on investigators' hardware, XNAT data import, system administrator support, one-on-one training and tutoring and a number of other specific services. The Core adopts a cost sharing approach, where services and computing resources beyond an established baseline level are billed to the investigators, with the NINDS investigators paying half the rate of other users

Neuroimaging methods are increasingly applied to all phases of neuroscience research ranging from preclinical studies in animal models to human patients. Even in an era of genomics and molecular medicine, neuroimaging remains essential for phenotyping brain structure and function, and for monitoring the evolution of brain disorders and their treatments. However, neuroimaging methodologies are constantly evolving, and their optimal use requires specialized methodological expertise. The Acquisition Core consolidates expertise in neuroimaging physics and engineering at the University of Pennsylvania to support a broad range of imaging methodologies relevant to the NINDS mission to reduce the burden of neurological disease. The primary supported acquisition strategy is MRI, which provides multiple contrast mechanisms relevant to brain structure and function. For this, the Acquisition Core leverages the availability of multiple research MRI systems at the University of Pennsylvania including human whole-body MRI systems operating at 3 Tesla and 7 Tesla and animal MRI systems operating at 3 Tesla, 4.7 Tesla and 9.4 Tesla. The Acquisition Core also supports optical imaging and transcranial magnetic stimulation (TMS) as well as a range of ancillary instrumentation used for stimulus delivery and biobehavioral response monitoring during neuroimaging. Supported technical expertise is used to provide consultation concerning specific imaging modalities, to implement new or improved imaging strategies, to provide troubleshooting and quality assurance for image artifacts, and to collaborate on multimodal image acquisition protocols. NNC users benefit from simplified access to methodological consultations and consolidation of technical expertise also improves efficiency and reduces the cost of neuroimaging research since most technical problems need not be solved separately for each project. Accordingly, neuroimaging application projects do not need to budget for extensive methodological support. Finally, consolidation of technical expertise fosters a highly collaborative environment for both Core personnel and Core users leading tonew approaches and research directions and rapid dissemination of methodological advances to the entire user community

Administrative Core Services. The Administrative Core provides organizational oversight for the NNC including scheduling, usage access and monitoring, dissemination, and regulatory support. Scheduling includes quarterly meetings of the Steering Committee, annual user meetings, as well as scheduling of scan time on NNC supported instruments and consultation through a web-based calendar system. A separate calendar is available for each resource and, includes quotas and transaction logging. The Administrative Coordinator is responsible for compiling usage data for the Steering Committee and for annual Progress Reports and will be responsible for the financial operations of the NNC, including collecting usage fees for computing. The Director and Administrative Coordinator also remain current on regulatory, administrative, and logistical issues relating to neuroimaging research and provide support and orientation to users on these topics. Standard verbiage for use in IRB applications and consent forms including verbiage on pregnancy testing and incidental findings is available for users, along with assistance in preparing and submitting regulatory documents to the IRB and CAMRIS for approval.

TR&D2: Brain Structure and Function  P.I: John Detre, MD Co-Investigators: Brian Avants, PhD and Ze Wang, PhD ABSTRACT TRD2 focuses on neuroimaging methods for use in basic and clinical neuroscience. Much of this work concerns the development and application of arterial spin labeled (ASL) perfusion MRI, a method initiated by our Regional Resource (1). ASL provides noninvasive quantification of tissue perfusion (blood flow). In brain, cerebral blood flow (CBF) quantifies cerebrovascular function, but CBF also serves as a means of quantifying neural function more generally through the tight coupling between CBF and regional neural activity (2, 3). Over the past project period, TRD2 further developed ASL MRI technologies and applications at 3T and at 7T. Additional neuroimaging technology developed by TRD2 included imaging of myelin and myelin water, susceptibility weighted imaging, and the development of new signal-processing strategies for both functional and structural MRI of the brain. TRD2 also collaborated with TRD1 on metabolic imaging of the brain and with TRD4 on optical monitoring of CBF and metabolism in the brain. In the upcoming grant period, we plan to continue these lines of inquiry, and to collaborate with TRD3 on short-TE imaging.

UNIVERSITY OF PENNSYLVANIA ALZHEIMER?S DISEASE CORE CENTER ABSTRACT: REVISION TO CREATE A NEW NEUROIMAGING CORE (CORE I) ADCC Director and Principal Investigator: John Q. Trojanowski, MD, PhD; Neuroimaging Core Leaders: John A Detre, MD and Paul A. Yushkevich, PhD This is an application for a revision of the University of Pennsylvania (Penn) Alzheimer Disease Core Center (ADCC) to establish an independent Neuroimaging Core (Core I). Currently, no dedicated neuroimaging infrastructure exists in Penn?s ADCC. Neuroimaging has emerged as a key approach for detecting and quantifying molecular neuropathology and resultant neurodegeneration in vivo, and neuroimaging biomarkers are contributing an increasing role to the diagnosis and prognosis of Alzheimer?s disease (AD) by staging patients along the AD continuum (i.e. preclinical through dementia). Advances in structural, functional, and molecular neuroimaging methodologies continue to expand the sensitivity, specificity, and appeal of these approaches, due in part to the non-invasiveness of image acquisition as compared to other potential biomarkers. The proposed Neuroimaging Core will create new infrastructure within the Penn ADCC to support state-of-the-art neuroimaging acquisition and informatics and provide ADCC investigators with access to resources and expertise needed to fully integrate neuroimaging metrics into clinical evaluation, clinical-pathological correlations, and genomic analyses. Aim 1 of the proposed Neuroimaging Core I will leverage leading neuroimaging expertise to support the development, acquisition, and analysis of state-of-the-art structural, functional, and molecular neuroimaging, including use of ultra-high-field imaging (7 Tesla) and novel PET ligands, and their applications as noninvasive biomarkers of AD neuropathology in the ADCC Clinical Core B cohort. As there is limited work linking quantitative measures of various proteinopathies and their interactions with three-dimensional structural brain changes across the cortical mantle, Aim 2 establishes linkage between in vivo neuroimaging and quantitative postmortem digital pathology via high-resolution MRI of intact autopsy brain specimens and image guided tissue sampling for digital pathology, in collaboration with Neuropathology Core D. Aim 3 will establish a new data infrastructure that will link multiscale in vivo, ex vivo, and digital microscopy imaging data with the extensive clinical, behavioral, and biofluid database maintained by Bioinformatics and Biostatistics Core C and enable flexible inquiry and discovery across clinical, pathological, genetic, and imaging modalities as well as facilitate data sharing. Training in Neuroimaging will also occur in collaboration with Education Core F.

Small vessel disease (SVD) is thought to be among the most prevalent disorders of the central nervous system and contributes a key mechanistic role in the syndrome of vascular cognitive impairment and dementia (VCID). A major challenge in the investigation of cerebral SVD is that small vessel integrity cannot be visualized in vivo. Instead, MRI lesions, most notably white matter hyperintensities, currently provide the most widely accepted biomarker of SVD. However, MRI white matter lesions represent downstream effects of SVD and further are not specific to ischemic brain injury. Noninvasive imaging strategies capable of detecting mechanistically- specific changes in small vessel structure or function would improve the identification and quantification of small vessel contributions to cognitive impairment and dementia and serve as biomarkers for monitoring the effects of therapeutic interventions in clinical trials. As we show in preliminary data, recent developments in the spatial resolution and sensitivity of arterial spin labeled (ASL) perfusion MRI now allow noninvasive quantification of cerebral blood flow (CBF) from the periventricular white matter (PVWM), which is supplied by the terminal distributions of long arterioles much less than 100 microns in diameter. PVWM-CBF accordingly represents a promising biomarker of small vessel perfusion, allowing quantification of small vessel functional integrity without spatially resolving individual arteries. Concomitantly, emerging optical methods such as optical coherence tomographic angiography (OCTA) also allow small vessels and even capillaries to be rapidly noninvasively imaged in the human retina using relatively inexpensive and increasingly widely available instrumentation. Both biomarkers hold the potential to detect mechanistically specific changes in small vessel structural or functional integrity prior to the development of brain lesions been formally established. However, while retina has been described as a ?window? to the brain, the relationship between OCTA measures of retina and brain structure and function has yet to be adequately tested. The overall goal of this proposal is to validate PVWM CBF and OCTA-derived microvascular density as bona fide biomarkers of human small vessel structure for use in clinical research. We will investigate the biological and technical determinants of PVWM CBF and OCTA-derived microvascular density, associate changes in retinal microvasculature with brain WML and perfusion, and preliminarily show their predictive value in SVD by correlating baseline measures with longitudinal changes in healthy and clinical cohorts. A multidisciplinary team of investigators with expertise in neuroimaging, retinal imaging, cerebral blood flow physiology, cerebrovascular disorders, aging, and dementia will collaborate to carry out this work.

The Department of Neurology, including the Division of Child Neurology, and the Center for Clinical Epidemiology and Biostatistics (CCEB) at the University of Pennsylvania propose to continue and enhance an innovative, rigorous, and successful two- to three-year research training program for clinicians in both adult and pediatric neurologic clinical epidemiology research. The training program focuses on mentored research with an experienced investigator that involves didactic training and the planning, design, conduct, analysis, and interpretation of an independent research project in neurologic clinical research, all intended to be the next step in a trainee's academic career preparing him/her for a career as an independently funded researcher. Trainees matriculate in the Master of Science in Clinical Epidemiology (MSCE) program. Didactic coursework consists of required courses in epidemiology and biostatistics, the basic sciences of high quality clinical research, methodology in neurologic clinical epidemiology, advanced epidemiology, protocol development, sophisticated biostatistics, and elective courses relevant to the trainees' methodologic interests. The training program is enhanced by journal clubs and clinical research conferences conducted by participating faculty; instruction in the responsible conduct of research; and a professional development series. The program will: 1) train clinicians to be rigorous and independent academic investigators able to use the range of approaches available in epidemiology to address research issues in neurology; 2) provide closely mentored research experiences with faculty preceptors in clinical epidemiology and neurologic medicine; and 3) strengthen the links between traditional epidemiology and neurology. Strengths of the proposed program are: 1) the long history of successful research training programs in the adult and pediatric neurology departments using the structure provided by the CCEB, including this training program; 2) the collaborative links that have been forged among faculty with interests in clinical research in neurology; 3) the comprehensive course offerings and research programs that are available to trainees; and 4) an extensive set of experienced and multidisciplinary faculty mentors with successful training records. The training program also brings together dozens of trainees from across all disciplines in medicine, which provides an ideal environment for collaborative learning and growth. Finally, The University of Pennsylvania and the Perelman School of Medicine promote an academic environment in which basic, clinical, and translational research are encouraged and viewed as attractive career paths for physicians.

SUMMARY This Research Training Program in Disease Oriented Neuroscience is designed to facilitate the transition between graduate training and a research-based career in neurology. R25 program trainees receive career mentoring from experienced clinician scientists in Neurology along with research mentoring from leading clinical neuroscience laboratory research faculty drawn from multiple departments and schools within the University of Pennsylvania. A focused educational program supplement laboratory research and includes training in translational research methods, applications, and the responsible conduct of research. The program is conducted in a large research-oriented institution with leading residency programs in adult and child neurology that trains some of the best candidates in the country and has an outstanding track record of fostering research oriented careers and trainee diversity. Over the past program period, the R25 pathway has been fully integrated into the residency training program and impacts all phases including residency application review, applicant visit and interviews procedures, advance mentorship and research opportunities for matriculated applicants, intensive support for the selection of mentors and the development of an R25 supplement request, and multiple levels of clinician scientist career development support. Between adult and child neurology, there are over 150 faculty members in our department, ranging from master clinicians, clinical educators, and clinical investigators to physician/scientists and basic scientists. Over 80% of graduating residents over the past 15 years have remained in academic medicine, and many have chosen careers as clinician scientists. The Hospital of the University of Pennsylvania and Children's Hospital of Philadelphia at the Perelman School of Medicine, where most of the clinical residency and fellowship training occurs, are located within a highly compact university campus in West Philadelphia spanning a radius of less than one half mile. Penn is also home to the first neuroscience institute in the country, the Mahoney Institute for Neurosciences, which consolidates almost 200 faculty members from 32 departments and six schools engaged in neuroscience research at Penn. The range of research opportunities for our R25 trainees can thus be extended to the wider neuroscience community inside and outside the Department of Neurology through co- mentorship of trainees with a diverse array of eminent scientists carrying out research relevant to the NINDS mission to reduce the burden of neurological disease.

Neuroimaging Core Project Summary Because of their tolerability, versatility, and spatial specificity, neuroimaging biomarkers are a prominent strategy used in AD/ADRD research to detect AD pathology, provide insights into disease mechanism and heterogeneity, track disease progression and, ultimately, monitor the efficacy of disease-modifying interventions. Neuroimaging methods can also noninvasively assess other neuropathophysiological mechanisms such as neurovascular insufficiency and neuroinflammation that are implicated as mechanisms and modulators of AD and therefore likely contribute to the heterogeneity observed in its risk, incidence, and progression. When linked to postmortem measures of proteinopathy burden, imaging measures can shed light on heterogeneity of AD/ADRD, allowing for discovery of in vivo signatures of ?pure AD? and concomitant non- AD pathologies. The Penn ADRC Neuroimaging Core will consolidate expertise in advanced neuroimaging methods and applications to support the acquisition and analysis of state-of-the-art multimodal MRI of brain structure and function, molecular brain imaging using PET, retinal angiography using optical coherence tomography (OCTA). The Neuroimaging Core will oversee the acquisition and analysis of standard MRI and PET scans used in defining preclinical AD based on amyloid, tau, and neurodegeneration (?A/T/(N)?) staging and for quantifying ischemic lesions in the brain. Additional unique features of the Neuroimaging Core include the use of ultra- high-field (7T) MRI both in vivo and for post-mortem imaging of intact hemispheres, the development methods for accurate image-guided sampling of post-mortem brain tissue allowing spatial linkage between digital pathology and in vivo morphometry, the development a data infrastructure linking imaging and non-imaging databases, novel MRI and OCT methods for quantifying brain structure and vascular function in ADRC research, and infrastructure to support the translation of novel PET tracers to clinical research in AD/ADRD. The Neuroimaging Core will also share imaging data collected at the Penn ADRC with the NACC Coordinating Center at the University of Washington and SCAN U24. The Neuroimaging Core will be highly integrated with other ADRC cores, providing access to advanced imaging and derived imaging metrics for the Clinical Core, collaboration on image analysis and databasing of image-based information with the Data Management and Statistics Core, linking in vivo and postmortem neuroimaging to neuropathology in conjunction with the Neuropathology Core, leveraging imaging as a means of linking genetic factors with structural and functional brain phenotype with Genomics Core, working with the Outreach Recruitment and Engagement Core to provide research updates about neuroimaging advances and promote participation in imaging studies, and providing education and training in neuroimaging through Research Education Component.