Marcus E. Raichle - US grants

The overall objective of this work is to further our understanding of the relationship between changes in brain cellular activity, caused by the functional activity of the brain in neurologically normal humans, and changes in blood flow and metabolism. Everyone agrees that the resting brain metabolizes glucose aerobically as its main source of energy. On the basis it was assumed that changes in the activity of the brain would be accompanied by parallel changes in blood glow, glucose utilization and oxygen consumption. It came as a considerable surprise when work with positron emission tomography (PET), supported previously under this program project [Fox, 1986#18][Fox, 1988#19], revealed parallel changes in glucose utilization and blood flow unaccompanied by changes in oxygen consumption. This important observation has not only catalyzed a re- evaluation of these relationships but also provided the physiological rationale for functional mapping of the human brain with magnetic resonance imaging (MRI). Despite the immense interest in functional mapping of the brain, uncertainty surrounds our understanding of these functionally-induced metabolic and circulatory changes. This project addresses two central questions concerning that understanding. First, do the changes in blood flow exceed those of oxygen consumption simply to maintain adequate tissue oxygen. To answer this question we propose to examine blood flow responses as a function of oxygen availability. Second, if glucose is used but only metabolized to lactate, why don't tissue lactate levels adequately reflect the increased glycolysis? To answer this question we propose to determine whether lactate egress from brain is facilitated in areas of increased functional activity. These experiments will provide valuable new information on the relationship of brain functional activity to brain energy metabolism in neurologically normal humans and a sounder scientific basis for functional brain imaging with PET and fMRI.

This is a tightly integrated, multidisciplinary effort involving fourteen investigators from seven divisions of the Washington University Medical Center. The three Core facilities, combined with the five Research Proposals, focus on normal relationships between brain and its vasculature, as well as the pathogenesis, diagnosis, and treatment of selected aspects of acute cerebrovascular disease. Evaluation of patients will involve the development and use of new tracer techniques involving the use of cyclotron-produced radiopharmaceuticals and positron emission tomography. In vivo tracer techniques will be used to examine exchange processes in the brain microvasculature as they might affect brain water content and, hence, volume. The role of platelets in cerebrovascular disease and platelet vessel interactions will be examined in vivo in man and an animal model using newly developed scanning techniques and radiolabeled platelets. The hemodynamic and metabolic criteria for and consequences of extracranial/intracranial arterial anastomosis will be examined using emission tomography and advanced tracer techniques. Finally, the role of vasospasm associated with subarachnoid hemorrhage will be studied in man using the same techniques.

meeting /conference /symposium; cerebrovascular disorders;

Anatomical studies suggest that the brain microvasculature is abnormal in patients with Alzheimer's disease. Three general abnormalities have been described. First, cerebral amyloid angiopathy (CAA), characterized by the presence of amyloid within brain capillary and arteriolar walls, is a frequent occurrence in patients with Alzheimer's disease. Second, several of "deformities" of cerebral arterioles and capillaries are described, including thickening of the capillary walls and loop formations. Finally, neurotransmitter systems within brain known to influence the microvasculature, namely the central noradrenergic and cholinergic systems, are severely affected in patients with Alzheimer's disease. Despite the presence of these abnormalities the hypothesis that the function of the cerebral vasculature is impaired in Alzheimer's disease has not been systematically evaluated. We propose to test that hypothesis by examining microvascular function using positron emission tomography (PET) to study: 1) resting state measurements of regional blood flow, vascular permeability-surface area product and metabolism; 2) the response of the vasculature to functional activation (e.g., visual or somatosensory stimulation); and (3) the relationship of functionally-induced vascular changes to changes in local glucose utilization. We will study 50 healthy elderly and 50 subjects with senile dementia of the Alzheimer type (SDAT) and compare their data to those of healthy young adults. The prospect of autopsy confirmation of vascular pathology is an added strength. Although PET is ideally suited to explore these issues it has been plagued by the problem of partial volume averaging due to brain atrophy. As a major component of this project we propose to develop and implement two new, innovative strategies of data analysis. The first is designed to correct PET regionally for the presence of atrophy using magnetic resonance imaging (MRI). The second performs image wide comparisons of PET data between subject groups after transforming all PET data to a common anatomical coordinate system using MRI information.

This is a tightly integrated, multidisciplinary effort involving fourteen investigators from seven divisions of the Washington University Medical Center. The three Core facilities, combined with the five Research Proposals, focus on normal relationships between brain and its vasculature, as well as the pathogenesis, diagnosis, and treatment of selected aspects of acute cerebrovascular disease. Evaluation of patients will involve the development and use of new tracer techniques involving the use of cyclotron-produced radiopharmaceuticals and positron emission tomography. In vivo tracer techniques will be used to examine exchange processes in the brain microvasculature as they might affect brain water content and, hence, volume. The role of platelets in cerebrovascular disease and platelet vessel interactions will be examined in vivo in man and an animal model using newly developed scanning techniques and radiolabeled platelets. The hemodynamic and metabolic criteria for and consequences of extracranial/intracranial arterial anastomosis will be examined using emission tomography and advanced tracer techniques. Finally, the role of vasospasm associated with subarachnoid hemorrhage will be studied in man using the same techniques.

computed axial tomography; computers; biomedical equipment resource; biomedical equipment purchase;

The Brain and its Vasculature represents the continuation of a 35-year study of the vasculature of the human brain and its relationship to brain function in health and disease. Because of the intimate relationship between brain function and the brain vasculature that has been uncovered by ourselves and others, studies of the vascular and metabolic responses to functionally-induced changes in neuronal activity provide a unique window into the functional organization of the human brain. Pursuit of this opportunity was greatly enhanced by the development of functional imaging techniques beginning in the 1970's with positron emission tomography (PET) which was pioneered in our laboratory with substantial support from this program project. This work has now been extended the magnetic resonance imaging (MRI) where it has expanded dramatically both in its sophistication and wide spread use. This competing renewal application carries forward many of the long standing interests and strengths of this program project. Stimulated by findings during the current grant period we now propose to examine more closely the relationship between brain blood flow and oxygen consumption as expressed in the oxygen extraction fraction (OEF). In this Project we will examine the hypothesis that the OEF can be used to define a baseline state of establishment of a baseline for a given area of the cerebral cortex. In Project we take advantage of what we have already learned from this approach. Using the OEF as a means of establishing a baseline level of activity we have identified areas along the anterior and posterior midline of the cerebral hemispheres whose activity is significantly higher than brain as a whole. Activity in these areas routinely declines with the onset of focused cognitive activity. This decline can, however, be attenuated by emotional arousal. Taken together with extant observations from others leads us to hypothesize the existence of a default system in cerebral cortex designed to assemble and evaluate information, both external and internal, of broad general relevance to the welfare of the individual. This system is an important determinant of our emotional and motivational state. Experiments are designed to test this hypothesis. In this Project we continue one of the major long standing strengths of this program project, the study of language instantiation in the human brain. New to the current proposal is the application of our knowledge and strategies to the study of language recovery in stroke patients. While seemingly different than the first two projects, one Project does, indeed, benefit through specific interactions with another Project and both the MR and Image Analysis Cores. Together the work in this program project captures the efforts of a tightly nit group of investigators who have worked closely together sharing common interest and techniques. The result has been a program with a long-standing record of success.

The overall objective of this work is to further our understanding of the functional organization of the normal adult human brain. Such an undertaking is feasible for two reasons, (1) PET can measure changes in blood flow in small regions of the normal human brain with a degree of accuracy unsurpassed by any other technique and (2) Changes in local blood flow accurately reflect changes in the activity of local ensembles of neurons. The vasculature provides a unique "window to the workings of the brain". Using PET measurements of local brain blood flow we will (1) identify multiple sensory areas in the human cerebral cortex of individual subjects in relation to their MRI-defined anatomy; (2) define, at least coarsely, the topographic organization of these areas; (3) Test stimuli which will serve to identify functional landmarks within the cerebral cortex; (4) determine how more complex functions like language are mapped on to these principal areas; (5) test the relationship of functional vs anatomical landmarks in primary sensory areas; and, if there is not a tight relationship between anatomical and functional landmarks, (6) test the use of functional landmarks as constraints in 3-dimensional warping algorithms in order to enhance signal averaging and comparisons of functional maps across subjects.

Functional brain imaging is based upon the assumption that localized changes in brain circulation(i.e., blood flow, blood volume, vascular mean transit time) and metabolism accurately reflect changes in neuronal activity. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are able to measure changes in circulation and metabolism safely and accurately to provide a unique window into human brain function. However, our understanding of the relationship of brain circulation and metabolism to neuronal activity is incomplete as is our understanding of the respective roles of PET and MRI in investigating these issues. It is the purpose of this project to employ PET, MRI and magnetic resonance spectroscopy (MRS) together in normal human subjects as well as patients with selected diseases to obtain a more complete understanding of the basis for the signals obtained and the respective role to be played by PET and MRI in functional brain imaging. This project compliments work in the project by powers which explores in detail the relationship of brain function to the delivery, transport and metabolism of glucose. This project will also be important to the work in the project by Peterson where the role of MRI has yet to be determined. Finally, this project brings together the expertise and resources of 3 major research groups whose combined experience in functional brain imaging with PET (Raichle an Powers), MRI (Haacke and Lin) and MRS (Ackerman, Neil and Bretthorst) is unique and should ensure that significant new scientific information regarding human brain function will be forthcoming from the proposed studies.

Modern functional brain imaging studies with both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) routinely demonstrated task-induced increases as well as decreases in brain activity. The increases (usually referred to as "activations") are generally thought to reflect increases in the local cellular activity of the brain. Decreases )sometimes called "deactivations") have remained an enigma for many. Some decreases related, simply, to the manner in which the imaging experiment was conducted. Thus, activity present locally in a control state and absent in a task state to which it is compared would, quite naturally, appear as a decrease. For many, this explanation is sufficient. However, a recurring group of decreases that appear to vary little in their locations across a broad range of experimental paradigm cannot so early be explained. During the presently funded grant period of this Program Project we have determined that among this group of recurring decreases are areas where true decreases from baseline activity occur (see this Project for further details). In this project we examine their possible functional significance. We focus on two midline areas: the posterior cingulate cortex and adjacent precuneus; and, the medial and the orbital frontal cortices. They are unique in that their baseline activity greatly excee3ds other areas of the cerebral cortex suggesting the presence of a default system designed to assemble and evaluate its emotional and motivational significance. Focused attention of any sort causes an immediate reduction in the activity of this system and in the amygdala (84). This is consistent with the common observation that focused cognitive activity attenuates emotional arousal and constrains goal directed activity. However, the degree to which activity within this system is suspended during task performance presents a balance between task demands and our emotional state. This is also consistent with the common observation that our emotional and motivation state, in turn, influence cognitive performance. It is the purpose of the experiments in this project to more clearly define the relationship of cognitive to emotion and motivation as expressed through changes in the activity of this default system about its baseline level of activity.

One the deepest mysteries of life is consciousness. Most people take for granted the fact that they are aware, that their waking experiences are framed by the construct of a "self" identity that remains consistent throughout life. But what are the physical, psychological, and cultural bases of consciousness? Some researchers believe that this construct is ultimately subjective, which means that it cannot be directly observed or measured. Some believe that consciousness can nonetheless be studied by indirect observation, while others have argued that the quality of subjective experience can never be studied by the scientific method.

With support of the National Science Foundation, Drs. Jack, Gallagher, and Raichle will join an international team of psychologists, psychiatrists, philosophers, and neuroscientists to investigate the empirical bases of consciousness. They will examine whether evidence for different conceptualizations of the self can be found in patterns of brain activity, and if so, whether their neuroscientific findings can help to further refine and expand our understanding of consciousness. Their work is focused on how the representation of self differs as a function of social and environmental contexts.

21+ years old; Accounting; Adult; Affect; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Behavior; Behavioral; Birth; Brain; Budgets; Cell Communication and Signaling; Cell Signaling; D-Glucose; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dependence; Development; Dextrose; Disruption; Encephalon; Encephalons; Event; Eye; Eyeball; Functional Magnetic Resonance Imaging; Glucose; Glycolysis; Goals; Human, Adult; Intracellular Communication and Signaling; MRI, Functional; Magnetic Resonance Imaging, Functional; Maintenance; Maintenances; Measures; Nervous; Nervous System, Brain; O element; O2 element; Oxygen; Parturition; Patients; Primary Senile Degenerative Dementia; Principal Investigator; Process; Programs (PT); Programs [Publication Type]; Research; Rest; Signal Transduction; Signal Transduction Systems; Signaling; Testing; adult human (21+); aerobic glycolysis; awake; biological signal transduction; blind; dementia of the Alzheimer type; design; designing; experience; fMRI; indexing; neural; primary degenerative dementia; programs; relating to nervous system; response; senile dementia of the Alzheimer type

Krebs'cycle; behavioral /social science research tag; brain imaging /visualization /scanning; positron emission tomography

DESCRIPTION (provided by applicant): The overarching hypothesis in this proposal is that brain glucose metabolism outside of oxidative phosphorylation (which we refer to as glycolysis) plays an important role in brain function in health and disease. Our interest in glycolysis arose from several observations made by us leading up to this proposal. Glycolysis accounts for 12 to15% of glucose metabolized by the adult human brain. A large fraction of this glycolysis occurs in a network of brain areas dubbed the brain's default mode network (DMN). The DMN consists of areas in medial and lateral parietal cortices, dorsal and ventral medial prefrontal cortex and the medial temporal cortices. It is noteworthy because it is more active in the resting state, is central to the functional organization of the brain, has the highest rate of glycolysis o any group of brain areas and is uniquely vulnerable to Alzheimer's disease. Because diabetes has emerged as a significant risk factor for Alzheimer's disease caused us to consider these two diseases together in terms of how glucose metabolism might not only serve to define a specific network of areas in the brain but also increase the vulnerability of these areas to Alzheimer's disease. In the experiments proposed, we ask how brain glycolysis and resting-state functional connectivity are regulated by age, sleep and systemic alterations in glucose homeostasis and insulin sensitivity. We specifically hypothesize that chronic hyperglycemia and insulin resistance as well as sleep deprivation increase glycolysis and A¿ release in brain areas, such as the DMN, that are heavily reliant on glycolysis, leading to increased A¿ deposition and accelerating the pathogenesis of AD. Project 1 and 2 will explore how brain glycolysis and functional connectivity in the DMN are regulated by systemic alterations in glucose homeostasis and insulin sensitivity in populations at risk for AD (older individuals and people with T2DM), and experiments in Project 3 will enable ideas tested in Projects 1 and 2 to be taken from the systems neuroscience level to the cellular and molecular level.

Project 2 is a direct extension of Project 1 utilizing the same controlled manipulations of glucose and insulin in the same normal young and older adults and patients with T2DM. The proposed experiments in Project 2 will employ fMRI BOLD imaging in the resting state (quiet wakefulness) to probe the effect of changes in glucose and insulin availability on the ongoing functional organization within and among brain systems and during the performance of a task designed to explore the acute mnemonic effects of hyperinsulinemia. To accomplish these aims we utilize fMRI BOLD imaging in two ways. First, we will evaluate the patterns of spatial coherence in the resting-state (quiet wakefulness) fMRI BOLD signal which have been shown to delineate relationships both within and among the major brain systems and their subcortical connections and to exhibit changes in patients with Alzheimer's disease particularly in relation to the brain's DMN. Second, we will evaluate regional, task-induced changes in the fMRI BOLD signal based on the observation that increasing insulin levels can improve cognitive performance, particularly in the memory domain. We propose to use a task, face-name recall, which can be implemented in the scanner, is commonly used in AD researchand exhibits stable test-retest reliability in older adults. Experiments in Project 2 also dovetail with and are greatly enriched by the studies in Project 3 which uses optical intrinsic signal (OIS) imaging a technique based on the same underlying physiology. fMRI and OIS are posited to depend on changes in glycolysis linked to blood flow and largely independent of oxygen consumption. We consider the changes they detect to be largely a glycolytically-driven, synaptic signal resulting in changes in hemoglobin oxygenation detectable by MRI and OIS imaging.

The scope of this program project requires a careful coordination of activities of all of the investigators and team members in order to achieve the overall objectives of the program. This is of special importance in our case because of the extensive use of common shared research facilities and office by the investigators on this program project. This has an added dimension due to the location of much of the research in the Mallinckrodt Institute of Radiology at Washington University. Housed within one facility are unequaled resources and personnel dedicated to brain research using positron emission tomography and magnetic resonance imaging. The main functions of the Administrative Core will be the coordination of effort across the several research groups and cores, effective interactions between the projects and the Internal and External Advisory committees, management of databases and Sharepoint sites for data archiving and communication, and oversight of all progress, regulatory paperwork and budgets. The close proximity of offices and scanners and the long-standing and excellent working relationships that exist among investigators and staff of the Program Project will facilitate this effort. Dr. Raichle will lead the Program Project's administrative activities with support from Dr. Hershey, administrative assistants and a bioinformatics support person as described in the Administrative Core Plan.

Administrative Core Summary The Neuroimaging Informatics and Analysis Center (NIAC), established in 2004, has been led since its inception by an active team of Principle Investigators and colleagues organized under the Administrative Core. The Core has established and adapted the Center's mission and strategy, and continues to respond to our supported investigators as the practice of neuroimaging evolves. As a result of these efforts, the NIAC serves as a vibrant focal point for WashU's neuroimaging community. The Administrative Core will focus on outreach, education, and supportive functions. Aim 1 is to provide organizational, logistical, and oversight functions for the NIAC. The Administrative Core will set the overall strategy for the Center and oversee its implementation by the Imaging and Informatics Core. The strategy will be established through active engagement with the Steering Committee and our user base. Outreach to current and potential users will use a multi-prong approach that includes presentations at departmental seminars, tracking of grant proposals and protocol registrations, and one-on-one meetings with faculty. New projects will be ?on boarded? by the Center PIs and the Center project management through a standardized process that includes documentation of project goals, timelines, and committed personnel. The development of new capabilities and effort on specific projects will be based on likely impact and potential for future growth. The ongoing success of the NIAC and its constituent parts will be actively monitored by the Steering Committee and NIH program management through key performance metrics that track use of specific core services. Finally, the Core will manage Center-wide budgeting and expenditures, including program income obtained through the Center's revenue-generating services. Aim 2 is to operate the NIAC clinical translation program, which facilitates the advancement of research imaging methods from the lab to clinical use. The program features a step-wise framework that defines procedures (project optimization, acquisition optimization, post-processing optimization, clinical pilot, clinical evaluation), key personnel, and metrics at each step in the process. Aim 3 is to operate the NIAC educational program. The Administrative Core will provide educational and training opportunities to the NIAC community. The education program will include a regular seminar series that runs throughout the academic year and features both local speakers and invited external faculty, multiday workshops focused on specific neuroimaging methods and software, and regularly scheduled training on NIAC tools. In addition, the Core will provide web-based documentation on the use of NIAC resources. Finally, we will provide ad hoc small group and one-on-one guidance tailored specifically to the needs of individual investigators and their staff.

Overall Center Summary The NINDS P30 center core at Washington University (WashU), which operates as the Neuroimaging Informatics and Analysis Center (NIAC), was established in 2004 to facilitate neuroimaging as a core research tool in the drive to better understand and treat neurological conditions and diseases. Neuroimaging-based research at Washington University covers the spectrum from preclinical small animal studies to large-scale clinical trials to translational use of novel imaging methods in the clinic. In recent years, this research has become more expansive to include larger patient cohorts, more complex imaging protocols, greater diversity of clinical, genetic, and behavioral measures, and more extensive quantitative post-processing and analysis. This research covers a diversity of neurological diseases and conditions, including stroke, traumatic brain injury, Parkinson's Disease, Alzheimer's disease, multiple sclerosis, and epilepsy. The overarching mission of the NIAC is to facilitate the full range of this research through a suite of innovative imaging physics, informatics, and analysis services supported by a rich consulting and educational program. With this continuation proposal, we will expand the Center's services to support the evolving practices of our investigators. Specific Aim 1 will facilitate large scale, interdisciplinary neuroimaging-based research by providing a comprehensive informatics infrastructure that provides data management and automated image processing services for small animal imaging and human imaging obtained at WashU facilities and in multi- center clinical studies. Specific Aim 2 will facilitate the development and adoption of new neuroimaging methods in clinical research and clinical practice by providing active expert consulting, MRI physics support, and advanced software development services. The NIAC will include three cores to achieve these aims. The Administrative Core will oversee the Center's operations and allocation of resources, operate an active outreach and education program, and ensure a high level of communication between the Center's faculty and staff and the neuroscience community. The Informatics Core will provide software and hardware to integrate the imaging facilities, provide database services, execute automated and semi-automated image processing pipelines, and share data within collaborative networks and the broader research community. The Imaging Core will provide direct user support through consulting services and training programs and will lead the effort to develop and transition new methods to the Center's users. The Center will be overseen by a Steering Committee composed of Center users and domain experts with deep and diverse experience. The three cores, under the Steering Committee's guidance, will work closely together to provide a comprehensive suite of services and resources to support the University's neuroimaging community.

PROJECT SUMMARY/ABSTRACT  In this project, we will evaluate the trajectory of changes in regional oxygen consumption and glucose use (total as well as the fraction devoted to aerobic glycolysis or AG) and in brain circulation through the course of preclinical AD to symptomatic AD in late middle-aged and older adults. It is currently established that AG is a marker of a group of metabolic functions which includes biosynthesis, neuroprotection, and apoptosis, which, in the context of the normal brain is involved in synaptic remodeling, learning and memory, and generation of energy for membrane pumps. AG is about 10-15% in the normal adult human brain, and it demonstrates more substantial changes compared to other measures of brain metabolism in response to physiological activation or pathophysiological challenges associated with brain diseases. Our cross-sectional observations in cognitively normal adults suggest that areas of the human brain targeted by AD pathology have uniquely high levels of AG, and higher levels of AG are associated with less PIB deposition, higher levels of CSF A?42 and better scores on cognitive tests. In our current project, we will determine the role of AG as a potential early biomarker of evolving AD pathology and predictor of cognitive decline. Our specific aims include estimation for the first time of AG in individuals with mild-to-moderate symptomatic AD combined with that in cognitively normal individuals to evaluate a hypothesis that low baseline AG will be associated with the subsequent development of AD pathology and cognitive decline. We will also determine the relationship between the rate of change in AG and rate of change in clinical assessments and biomarkers of AD. In most cases, this information will be combined with the previously collected data in the same individuals to provide a multipoint trajectory over time. These longitudinal assessments will allow us to evaluate changes in AG and other PET measures of metabolism and circulation during the transition from no AD pathology to preclinical AD, and through the preclinical stages to symptomatic AD. We will evaluate the hypothesis that AG changes prior to other parameters, and that the rate of change in AG will predict progression in AD pathology and cognitive decline. Our work may not only expand significantly our understanding of the role of glucose in brain function beyond providing energy via oxidative phosphorylation, but also provide important new insights into the pathophysiology of AD and neuroprotective potential of AG. This project is innovative because it proposes to combine different biomarkers of AD to address novel questions, in vivo, in humans to produce findings relevant to both clinical disorders and fundamental human neurophysiology. The methods chosen, with which our group has substantial expertise, will allow us to study intrinsic regional brain activity and energy utilization, in vivo, in humans, which appear to be associated with the regional development of AD pathology. This project will evaluate a potential of AG as a highly specific biomarker of synaptic function, and provide novel insight into the development and control of the efficacy of preventive treatments aimed to reduce AD pathology by modulating synaptic function.