Brain Damage - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

BRAIN DAMAGE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R EFERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright ©2003 by ICON Group International, Inc. Copyright ©2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Brain Damage: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83773-2 1. Brain Damage-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on brain damage. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON BRAIN DAMAGE ........................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Brain Damage ............................................................................... 4 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 60 CHAPTER 2. NUTRITION AND BRAIN DAMAGE ............................................................................ 105 Overview.................................................................................................................................... 105 Finding Nutrition Studies on Brain Damage ............................................................................ 105 Federal Resources on Nutrition ................................................................................................. 107 Additional Web Resources ......................................................................................................... 107 CHAPTER 3. ALTERNATIVE MEDICINE AND BRAIN DAMAGE ...................................................... 109 Overview.................................................................................................................................... 109 National Center for Complementary and Alternative Medicine................................................ 109 Additional Web Resources ......................................................................................................... 111 General References ..................................................................................................................... 113 CHAPTER 4. DISSERTATIONS ON BRAIN DAMAGE ........................................................................ 115 Overview.................................................................................................................................... 115 Dissertations on Brain Damage................................................................................................. 115 Keeping Current ........................................................................................................................ 116 CHAPTER 5. PATENTS ON BRAIN DAMAGE .................................................................................. 117 Overview.................................................................................................................................... 117 Patents on Brain Damage .......................................................................................................... 117 Patent Applications on Brain Damage ...................................................................................... 144 Keeping Current ........................................................................................................................ 155 CHAPTER 6. BOOKS ON BRAIN DAMAGE ...................................................................................... 157 Overview.................................................................................................................................... 157 Book Summaries: Federal Agencies............................................................................................ 157 Book Summaries: Online Booksellers......................................................................................... 159 The National Library of Medicine Book Index ........................................................................... 165 Chapters on Brain Damage ........................................................................................................ 166 CHAPTER 7. MULTIMEDIA ON BRAIN DAMAGE ........................................................................... 167 Overview.................................................................................................................................... 167 Video Recordings ....................................................................................................................... 167 Bibliography: Multimedia on Brain Damage............................................................................. 168 CHAPTER 8. PERIODICALS AND NEWS ON BRAIN DAMAGE ........................................................ 169 Overview.................................................................................................................................... 169 News Services and Press Releases.............................................................................................. 169 Newsletter Articles .................................................................................................................... 172 Academic Periodicals covering Brain Damage .......................................................................... 172 CHAPTER 9. RESEARCHING MEDICATIONS ................................................................................... 175 Overview.................................................................................................................................... 175 U.S. Pharmacopeia..................................................................................................................... 175 Commercial Databases ............................................................................................................... 176 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 181 Overview.................................................................................................................................... 181 NIH Guidelines.......................................................................................................................... 181 NIH Databases........................................................................................................................... 183 Other Commercial Databases..................................................................................................... 187 APPENDIX B. PATIENT RESOURCES ............................................................................................... 189

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Overview.................................................................................................................................... 189 Patient Guideline Sources.......................................................................................................... 189 Finding Associations.................................................................................................................. 195 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 197 Overview.................................................................................................................................... 197 Preparation................................................................................................................................. 197 Finding a Local Medical Library................................................................................................ 197 Medical Libraries in the U.S. and Canada ................................................................................. 197 ONLINE GLOSSARIES................................................................................................................ 203 Online Dictionary Directories ................................................................................................... 203 BRAIN DAMAGE DICTIONARY.............................................................................................. 205 INDEX .............................................................................................................................................. 287

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with brain damage is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about brain damage, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to brain damage, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on brain damage. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to brain damage, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on brain damage. The Editors

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the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON BRAIN DAMAGE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on brain damage.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and brain damage, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “brain damage” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Otoacoustic Emissions and Auditory Assessment in Infants at Risk for Early Brain Damage Source: International Journal of Pediatric Otorhinolaryngology. 58(2): 139-145. April 27, 2001. Contact: Available from Elsevier Science. P.O. Box 945, New York, NY 10159-0945. (888) 437-4636. Fax (212) 633-3680. E-mail: [email protected]. Summary: The importance of early hearing screening has long been recognized, as the prognosis for the hearing impaired child is improved when the diagnosis is made as early as possible, and the intervention is begun immediately. For clinical screening of hearing impairment, the recording of otoacoustic emissions (OAE) was recommended. The authors of this article hypothesize that some risk factors for early brain damage are

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at the same time risk factors for dysfunction of the auditory system; hence, infants at risk for brain damage have hearing impairment more frequently than the rest of the population of the same age. The authors report on their study of the role of OAE testing during the assessment of auditory function in 110 infants at risk for brain damage. Spontaneous OAE was detected in 38.2 percent of the infants; evoked OAE was registered in 27.3 percent of the infants. The testing had to be repeated in 32.7 percent of the infants. Up to 32.7 percent of infants at risk for brain damage were found to have hearing loss. Conductive hearing loss was discovered with 25.4 percent of infants, and eight (7.3 percent) had sensorineural hearing impairment (SNHL). In the group of infants with only risk factors, 3.6 percent had SNHL, and in a group with abnormal motor development, there were 18.5 percent with SNHL. The authors conclude that infants at risk for brain damage have more frequently impaired auditory function than their peers. For this reason, it is vital to focus attention on the hearing condition when dealing with this population. 1 table. 37 references. •

Dementia in Left Brain Damage Source: Clinical Gerontologist. 17(4): 13-22. 1997. Summary: This journal article describes a study of the Spatial Location Test (SLT), a nonverbal test on which aphasic patients have been shown to perform as well as nonaphasic controls. It was hypothesized that, in patients without left brain damage, scores on a test involving visual memory would correlate highly with scores on a dementia test involving verbal skills. In patients with left brain damage, the correlation would be weaker. For this study, the SLT was modified for low scorers. The modified SLT and the Mental Status Questionnaire (MSQ), an established dementia test that is primarily verbal, were administered to two groups, each likely to include members with dementia. One group, 14 inpatients (mean age, 70 years) on a geriatric psychiatry unit, had no evidence of left brain lesions. The other group of 15 patients (mean age, 63 years) were known to have left brain lesions. Among the patients without left brain lesions, there was no significant difference between mean scores (percentage of errors) on the SLT and the MSQ, and the scores on the two tests were strongly correlated. Among patients with left brain lesions, mean scores on the MSQ were significantly higher than those on the SLT, and the correlation between the two scores was weak. Clinical observations suggested that the SLT measured some kind of mental ability that remained after the power of speech was lost. The authors conclude that the modified SLT may be useful in identifying dementia in patients with aphasia. Copies of the SLT and MSQ are appended. 1 table, 17 references.

Federally Funded Research on Brain Damage The U.S. Government supports a variety of research studies relating to brain damage. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions.

2 Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to brain damage. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore brain damage. The following is typical of the type of information found when searching the CRISP database for brain damage: •

Project Title: 3D MR SPECTROSCOPIC IMAGING OF THE NEWBORN BRAIN Principal Investigator & Institution: Vigneron, Daniel B.; Associate Professor; Radiology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2001; Project Start 05-FEB-2001; Project End 31-JAN-2006 Summary: (Verbatim from the Applicant's Abstract): Brain injury in term and preterm neonates is a serious problem. Of the approximately 42,000 infants born yearly in the United States with a birth weight less than 1500 g, approximately 85 percent survive and, of these, 5-10 percent exhibit major motor deficits and another 25-50 percent exhibit developmental and visual difficulties. Hypoxia and ischemia frequently occur during the birth process; however, the amount of brain damage in these patients and the longterm neurologic outcome varies considerably from patient to patient. There is a need, particularly in this group, to identify new clinical diagnostic tools that will improve early prediction of neurodevelopmental abnormalities and therefore allow for pharmacological interventions. The goal of this bioengineering research project is to develop and implement advanced Magnetic Resonance spectroscopic imaging techniques to detect the distribution of metabolite levels throughout the brain of neonates. Studies by ourselves and others have indicated an important role for single voxel MRS in the assessment of the neurologic status of neonates, especially premature infants and those with suspected neonatal hypoxia. However, these techniques provide very limited coverage of the brain and at poor spatial resolution. In this study, we propose to develop and optimize MRSI techniques to provide, for the first time, a study of the 3D distribution of metabolite levels in the newborn brain. This information will define the normal variation in metabolite levels with anatomic location and postconceptional age. The database of normal MRSI spectra will improve our understanding of brain development and provide a reference for detecting abnormal metabolism in neonatal patients with neurologic damage. Current methods are inaccurate for assessing the cerebral metabolism of newborns. Through this project, we aim to develop a noninvasive metabolic imaging technique to address this important problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ABNORMAL WATER METABOL IN TYPE 1A ANGIOTENSIN RECEPTOR DEFICIENT MICE: MUTANT Principal Investigator & Institution: Oliverio, Michael I.; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001 Summary: The goal of this project is correlative MR and optical histology of a model of brain damage induced by AET. Recent results have demonstrated neuronal damage detected by MRM in brain specimens from animals treated with DOM. Some of the lesions seen in the MRM specimens were not evident in conventional optical sections with H&E and Nissl stain. If these results can be demonstrated in other models of

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disease, the implications are enormous. Simply put, this suggests that MRM can detect lesions not seen in conventional histology. This is consistent with other recent evidence in the Center. A total of 9 specimens will be scanned. These are 1/2 the brains of rats that have been treated with AET. The other half brains have already been sectioned and analyzed with conventional histology. Six of these specimens show significant damage in four different nuclei: Superior Olive, trapezial nucleus, red nucleus, facial nucleus. Damage ranges from 10% of the nucleus to as much as 97% of the nucleus. We will scan the second 1/2 brain with 2 protocols: I FSE -TR=1.5sec; TE=50 ms; Nechos=8; fovz=fovy=10 mm; fovx=20 mm; matrix (z,y,x)=256x256x128; nex=2 (Total time 6.8 hrs) II GRASS TR=100 ms.TE=3 ms, alpha=350 , same fov matrix as I, nex=4 (total time =3.64 hrs) We will section the specimens after MR and compare specific regions of interest with quantitative morphometry to describe % cell damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACUTE BRAIN INJURY AFTER SUBARACHNOID HEMORRHAGE Principal Investigator & Institution: Bederson, Joshua B.; Neurosurgery; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 31-DEC-2001 Summary: (Applicant's abstract): The applicant's long-term goal is to develop a program of laboratory research that parallels the clinical problems of patients with cerebrovascular disorders. One of the most important of these is the lack of treatment options for patients who have suffered a severe subarachnoid hemorrhage (SAH). Although progress has been made in our treatment of the delayed consequences of SAH, acute SAH-induced brain injury is the primary cause of morbidity and mortality from SAH, and no effective treatment exists. In this proposal we utilize a multidisciplinary approach to examine the pathophysiology and pharmacological treatment of acute brain injury after experimental SAH. The investigators hypothesize that: 1)acute brian injury after SAH (as opposed to delayed ischemic damage) is caused by constriction of cortical microvessels, 2) acute vasoconstriction in this setting is due to a multifaceted central adrenergic pathways, and 3) SAH-induced alteration of these pathways is pharmacologically treatable within a clinically relevant time frame. The problem will be approached using a novel rat model of SAH developed in this laboratory. The physiological predictors of early mortality after SAH (cortical blood flow and cerebral perfusion pressure) will be compared with the factors known to influence (or be influenced by) vasodilatory and vasoconstrictive tone. These will include: a) the activity of nitric oxide synthase (NOS) measured by a modified citrulline assay, b) the extracellular concentrations of catecholamines and glutamate measured by cerebral microdialysis and high performance liquid chromatography, and c) histological evidence of acute vasoconstriction and ischemic brain damage. We will determine if acute cerebral ischemia, early mortality rate, and ischemic histological damage can be reduced by enhancing vasodilatory tone and inhibiting vasoconstrictive tone with the NO donor sodium nitroprusside or the cGMP-specific phosphodiesterase inhibitor Zaprinast, the nonspecific c-AMP phosphodiesterase (PDE) inhibitor papaverine hydrochloride or the type III cAMP-specific PDE inhibitor Milrinone, and for alpha adrenergic blockade the selective alpha 1 antagonist Benextramine. In addition, we will administer the NOS inhibitor NG-monomehtyl-L-arginine (L-NMMA) which, if our hypotheses are correct, should increase vasoconstriction and worsen outcome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AFFECTIVE AND CONATIVE CHANGES IN ALCOHOLISM Principal Investigator & Institution: Berman, Marlene O.; Professor of Psychiatry and Neurology; Psychology; Boston University Charles River Campus 881 Commonwealth Avenue Boston, Ma 02215 Timing: Fiscal Year 2001; Project Start 01-DEC-1996; Project End 30-NOV-2001 Summary: This is an application for an ADAMHA Senior Scientist Award (SSA). The SSA would permit the PI (a) to devote all of her research efforts to alcoholism; (b)to expand her research and mentoring activities concerned with gender issues in alcoholism; and (c) to gain valuable experience with structural and functional neuroimaging techniques. In conjunction with 2RO1 AA 07112-09, investigations are planned to examine changes in affect (emotion) and conation (intention) in abstinent alcoholics. Secondary aims of the research are to expand studies of age-related changes and gender differences in emotional and intentional functions. The importance of the research is fourfold: (1) Putative sites of alcohol-related brain damage involve separate frontal systems which are tied to different perceptual/cognitive aspects of emotional and intentional behaviors; (2) gender differences in alcohol- related neurobehavioral functions are ripe for experimental exploration; (3) the literature on whether emotional changes have reciprocal effects on perception and cognition in alcoholism is equivocal and controversial; and (4) even though affective and conative abnormalities have been clinically apparent in alcoholic groups, neuropsychological studies have focused primarily on cognitive changes unrelated to emotion and intention. In the proposed experiments we will enlist the participation of right- handed male and female research subjects ranging in age from 20 to 75 years. The experimental groups will include abstinent alcoholics with and without Korsakoff's syndrome. Patterns and levels of performances by the alcoholics will be compared to those of age-matched nonalcoholic subjects, in order to evaluate the ways in which behavioral consequences of aging and alcoholism are parallel, divergent, or interactive. Additionally, patients with rightfrontal or bilateral frontal lobe damage from cerebrovascular accidents will provide the necessary control comparisons for neurobehavioral changes linked directly to focal brain damage. These groups were chosen specifically to clarify frontal system contributions to deficits of Korsakoff and non-Korsakoff alcoholics. We also will be able to evaluate hypotheses about greater right- than left-hemisphere functional decline in the alcoholic and aging groups, and in women compared to men. It is expected that results of the proposed studies will show clear evidence of frontal-mediated affective and conative changes in alcoholics (most notably in the Korsakoff patients), but that these changes will not be conspicuous in aging populations uncomplicated by alcoholism. By contrast, certain aspects of perceptual functioning will be compromised by aging - whether or not a history of alcohol abuse exists. Finally, women will display different performance patterns than men. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AGING AND THE CHOLINERGIC SYSTEM ON ATTENTION AND TIMING Principal Investigator & Institution: Pang, Kevin Ch.; Associate Professor; Psychology; Bowling Green State Univ Bowling Green 220 Mcfall Ctr Bowling Green, Oh 43403 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The elderly tend to be afflicted with impairments of several cognitive processes, including a decreased ability to pay attention, perform multiple tasks, and to time short intervals. Some models suggest a close interaction of

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timing and attention. The proposed studies hypothesize that attention and timing involve similar brain regions, in particular motor areas in the frontal lobe. In addition, it is predicted that dysfunction of the frontal motor areas is responsible for the age-related impairments in attention and timing. This dysfunction is due, in part, to the loss of cholinergic neurons of the nucleus basalis magnocellularis (NBM). The proposed studies do the following: 1) examine the effects of damage to motor cortex and NBM projections to motor cortex on attention and time estimation, 2) compare age-related changes of attention and timing in rats and humans, 3) examine the relationship between agerelated loss of NBM neurons and impairments in attention and timing, and 4) investigate the effects of aging and brain damage on attention-related neuronal activity in motor cortex. The proposed behavioral studies with rats and humans involve similar versions of a simultaneous temporal processing (STP) task. In the STP task, subjects' learn to associate auditory and visual cues with short and long fixed time intervals, and are then tested on their ability to produce/estimate this time interval under different attentional demands. In a focused attention condition, only one cue is presented to subjects. In a divided attention condition, both cues are presented and must be attended to in order to respond correctly. The focused attention condition serves as a baseline measure of performance. The central empirical question concerns how aging and lesions (in rats) affect timing performance in divided attention conditions, relative to focused attention conditions. Model fits using scalar-expectance theory facilitate comparison between the human and rat behavioral data and potentially provide a functional interpretation of the effects of aging and lesions on focused and divided attention. Overall, the studies in this proposal will enhance our knowledge of the brain systems participating in attention and timing. Importantly, new information will be revealed that will elucidate the neural mechanisms responsible for age-related impairments in attention and timing. This new knowledge will provide directions for the development of treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AGING BRAIN--CEREBROVASCULAR MECHANISM & AMYLOID BETA Principal Investigator & Institution: Zlokovic, Berislav V.; Professor and Director; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 30-APR-2004 Summary: This proposal represents investigators from the University of Southern California, Columbia University and State University of New York at Stony Brook Schools of Medicine who participate in a multi-disciplinary program on Cerebrovascular Mechanisms in the Aging Brain. The goal of the program is to advance current knowledge regarding the role of vasculature in the aging brain and major CNS disorders in elderly that predispose to cerebrovascular amyloidosis (e.g., Alzheimer's Disease and related amyloid-beta-peptide (Abeta) disorders, such as hereditary cerebral hemorrhage with amyloidosis Dutch type), Abeta-related vascular injury, brain damage and stroke. We will apply concepts and techniques developed in cerebrovascular biology, blood-brain barrier (BBB) and cerebrospinal fluid physiology, molecular biology, molecular genetics, transgene mice with age-dependent vascular risk factors, and tissues and cell cultures from patients diagnosed with AD. The program consists of five Research Projects and three Core resources. Project 1, Dr. Zlokovic will study the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project the role of BBB and brain clearance in regulating Abeta concentrations in cerebral vessel wall and brain. Project 2, Dr. Van Nostrand will study

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Abeta production by cerebrovascular smooth muscle cells in relation to amyloidosis. Project, Dr. Stern will study the role of receptor for advanced glycation and end products in acute and chronic cerebrovascular perturbation caused by Abeta and strokerisk factors. Project 44, Drs. Schreiber and Zlokovic will delineate the roles of Abeta dn amyloid in vascular hemostasis in relation to ischemic or hemorrhagic stroke. Project 5, Drs. Kalra and Rhodin will study the role of Abeta in migration of monocytes across the BBB and vascular wall. Core A is the administrative facility. Core B, Dr. Mackic and Kim will provide animal and cell culture facility. Core C, Dr. Miller will provide neuropathologic analysis. The integrated and complementary scientific research projects will provide a molecular and therapeutic rationale to prevent accumulation of Abeta and formation of amyloid in cerebral blood vessels and brain, and counteract agedependent mechanisms responsible for abnormal vascular responses, injury and brain damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BEHAVIOR MEDIATED NEURAL PLASTICITY AFTER BRAIN DAMAGE Principal Investigator & Institution: Jones, Theresa A.; Psychology; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 15-APR-1997; Project End 31-AUG-2001 Summary: Research in the last three decades has made enormous progress in demonstrating and elucidating plasticity in the central nervous system of ~adult animals~. Two important types of proof of this plasticity arise from studies of damage to the brain and from studies using manipulations of behavioral experience. Studies of the effects of brain damage have shown that regions connected to the site of damage undergo reactive neuronal growth and reorganization. Studies manipulating behavioral experience have shown that regions involved in those behaviors also undergo neuronal changes. The emphasis of the present proposal is that these two types of plasticity may be interactive following brain damage. It is obvious that brain damage can produce behavioral changes. Based on abundant evidence that changes in behavioral experience can lead to central neuronal structural changes, it seems reasonable that these behavioral changes may influence and interact with plastic neuronal responses that occur after brain damage. Recent research has revealed a novel examples of neural plasticity following brain damage which seems o be mediated by behavioral changes. Unilateral lesions to the forelimb representation area of the sensorimotor cortex (Flsmc) in adult rats leads to impairments in the use of the forelimb contrlateral to the damage. Animals appear to compensate for these impairments, in part, by developing an over-reliance on the forelimb ipsilateral to the damage (the non-impaired forelimb). Examination of neurons and synapses within the forelimb motor cortex opposite the damage and the non-impaired forelimb revealed a marked dendritic growth and synaptogenesis. This neural plasticity appears to be mediated by the post lesion changes in the use of forelimbs and to be facilitated by the presence of a lesion in the opposite cortex. The processes underlying this behaviorally mediated neural plasticity are not understood and are potentially very important for ongoing attempts to understand brain adaptation to brain injury and to identify processes which can be manipulated to facilitate functional recovery. The proposed studies will (1) characterize structural (neuronal and glial) and connectional plasticity of the motor cortex and cerebellum following unilateral Flsmc lesions using quantitative electron microscopy, immunocytochemistry and anatomical tract tracing methods (2) relate these changes to behavioral changes using sensitive behavioral measures and behavioral manipulations, and (3) manipulate, and

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perhaps facilitate, adaptive neuronal and behavioral changes using complex motor skills training as "therapy" after the lesions. These studies may be of relevance to post-injury rehabilitation and neurolgical disorders in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BLOOD PRESSURE, COGNITIVE FUNCTION & MRI IN OLDER ADULTS Principal Investigator & Institution: Goldstein, Iris B.; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 15-APR-1994; Project End 30-NOV-2003 Summary: The present proposal is a longitudinal study of 135 elderly men and women who were first studied years earlier. The initial data indicated that among healthy individuals, aged 55-79 years, with relatively low blood pressures, 24-hour ambulatory blood pressure and heart rate (both level and variability) were significantly related to cognitive tests and signs of subtle brain damage as assessed by magnetic resonance imaging (MRI). The primary goal of this follow-up study is to demonstrate how ambulatory blood pressure technology can be useful in predicting future changes in brain and cognitive function which may be associated with apparent clinical problems but predate stroke and other cerebrovascular pathology. We will look at blood pressure and heart rate level and variability during two entire 24-hour periods, focusing on variability and level during wake and sleep, and the amount of fall from wake to sleep. In order to determine changes that have occurred, many procedures will be repeated, including a complete medical exam, casual blood pressure and heart rate measurement, and neuropsychological testing (sampling such critical areas as memory, attention, abstract reasoning, and cognitive flexibility. From MRI data we will determine both focal (T2 hyperintense lesions) and non focal (atrophic) brain changes. On the basis of our current findings, we expect that with the passage of time those individuals with higher casual and ambulatory blood pressure, greater blood pressure variability, and a smaller drop in blood pressure and heart rate during sleep will be likely to exhibit decrements in neuropsychological test performance and increases in T2 hyperintensities and brain atrophy. The fact that healthy, elderly individuals with normotensive blood pressure levels may be at risk for cognitive deficits and brain damage has clear implications for decisions regarding the appropriate level and variability of blood pressure to treat in elderly. Also, there is a need for future studies to concentrate on drug and behavioral methods which decrease variability of blood pressure and maintain 24-hour blood pressure control, in addition to decreasing casual blood pressure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BRAIN CELL APOPTOSIS AFTER INTRACEREBRAL HEMORRHAGE Principal Investigator & Institution: Lo, Eng H.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 31-JAN-2004 Summary: (Verbatim from the Applicant's Abstract) Intracerebral hemorrhage constitutes up to 15 percent of all strokes. Yet, compared to ischemic strokes, the mechanisms of brain cell damage after hemorrhage remain relatively unexplored. Prognosis after hemorrhage is less favorable compared to ischemia. Furthermore, with the risks of hemorrhage associated with thromblytic therapy, it becomes increasingly important to understand the mechanisms of brain damage after hemorrhage. In this proposal, we will use rat and mouse models of intrastriatal hemorrhage to test the

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overall hypothesis that cell death after hemorrhage is mediated, in large part, by apoptosis. Our preliminary data show that (i) parancymal ischemia accompanying hemorrhage is mild therefore this may favor apoptotic pathways of cell death; (ii) extensive internucleosomal DNA fragmentation occurs in cells surrounding the hemorrhage; (iii) DNA fragmentation post-hemorrhage is reduced by caspase inhibitors; and (iv) pro-apoptotic factors are released into extracellular space after hemorrhage and can be recovered by in vivo microdialysis. Our specific aims are: 1) establish the spatial and temporeal profile of apoptosis after hemorrhage, 2) quantify the levels of parenchymal ischemia adjacent to the hemorrhage and assess the accompanying release of pro-apoptotic factors (Fe2+, thrombin, FasL, TNF) into extracellular space, 3) test the efficacy of caspase inhibitors for reducing brain cell death after hemorrhage, and 4) investigate possible interactions between tissue plasminogen activator (tPA) and hemorrhagic apoptosis. For the 1st aim, we will map morphological, biochemical, and molecular markers of apoptosis after intracerebral hemorrhage. For the 2nd, parenchymal ischemia will be assessed with in vivo MRI methods that measure hemorrhagic progression, blood-brain barrier breakdown, and perfusion deficit. Additionally, we will use in vivo microdialysis to sample extracellular space after hemorrhage and assess the pro-apoptotic activity of Fe2+, thrombin, FasL and TNF with in vitro cultured cells. Experiments will also be performed in TNFR knockout and MnSOD overexpressing transgenic mice. For the third aim, we will characterize the therapeutic window for the caspase inhibitor zVADfmk, compare it with the free radical spin trap alphaPBN, and explore the benefits of combination therapy. Finally, since hemorrhage can be a serious complication of tPA therapy, we will examine as our 4th aim, the effects of tPA on apoptosis in our models. These proposed 3expeiments are expected to synergize with ongoing work in our labs that examine mechanisms that mediate tPA-induced hemorrhage in ischemic stroke (Lo, R01NS37074) and the efficacy of caspase inhibition for cerebral ischemia (Moskowitz, R01NS37141). Results may be used to improve the clinical management and treatment of intracerebral hemorrhage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAIN DAMAGE EFFECTS ON LANGUAGE PROCESSING Principal Investigator & Institution: Swinney, David M.; Professor; Psychology; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 92093 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 31-DEC-2002 Summary: (adapted from the applicant's abstract): This proposal seeks to investigate the nature and neurological organization of language-based communicative capacities. It continues the investigator's long-standing aim to provide a detailed functional analysis of language processing in real-time. Studies are aimed at discovering how language comprehension is organized in the brain at the lexical, sentential (structural), and discourse levels. Normal and aberrant processing is examined at each level with consideration of effects of aberrant processing at one level on another. Ten series of experiments are proposed, two at the lexical level, five at the sentential level, and three at the discourse level. These studies are designed to provide a window on a wide range of language processes and how they interact and support one another (or fail to). The guiding hypothesis is that focal brain damage can disentangle cognitive subsystems that normally are inextricably intertwined by examining on-line moment by moment changes in activation, usually of lexical items, under manipulation of differing lexical, structural, or discourse factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BRAIN PATHOGENESIS

DEVELOPMENT

&

ETHANOL:

MICROGLIAL

Principal Investigator & Institution: Kane, Cynthia Jm.; Associate Professor; Anatomy; University of Arkansas Med Scis Ltl Rock 4301 W Markham St Little Rock, Ar 72205 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2003 Summary: Intervention in the extensive CNS pathology that underlies fetal alcohol syndrome is a high priority for alcohol researchers and is the long-term goal of this laboratory. There is no treatment for the brain damage associated with fetal ethanol exposure since the cellular and molecular mechanisms by which ethanol causes developmental neuropathogenesis are not yet understood. Although many years of study have focused on the neuronal and macroglial pathology caused by ethanol, the impact of ethanol upon an important, major cell type in the brain - the microolial cell has not been probed until these recent studies. This is surprising since ethanol damage to microglia may produce serious consequences within developing neuronal populations. Microglia communicate directly with neurons and the immune system to influence neuronal survival and function. They are the first line of defense against CNS insults, are the principal immune cells within the brain, and are active in cytokine secretion, reactive oxygen species secretion, antigen presentation and phagocytosis. Pilot studies reveal that damage to microglia occurs at ethanol concentrations far below that required to cause direct neuronal death. Parallel studies in the cerebellum and cultures of microglia have led to the HYPOTHESIS that ethanol pathogenesis in microglia occurs via specific cellular mechanisms: (1) ethanol inhibits microglial genesis and survival, (2) ethanol suppresses microglial maturation to further reduce the population of mature microglia, (3) the activity and functionality of microglia are impaired as a result, and (4) since there is no turnover of microglia, the impaired microglial functionality persists in the adult. This study will define the mechanisms of ethanol pathogenesis within the microglial population. A causal relationship between microglial pathology and neuronal toxicity will be defined. The critical period of microglial sensitivity to the teratogenic effects of ethanol will be determined. The acute, transient or persistent nature of ethanol pathogenesis within the microglial population will be distinguished. The molecular mechanisms of ethanol activity will be identified. The intracellular signaling pathways underlying ethanol activity will be manipulated in order to block ethanol pathogenesis in microglia. Block of ethanol-induced microglial pathology may provide a new opportunity to intervene in the brain damage caused by fetal ethanol exposure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAIN INJURY DURING CPR PREVENTED BY VASCULAR NITROXIDE Principal Investigator & Institution: Hsia, Carleton Jc.; Synzyme Technology, Inc. 1 Technology Dr, E-309 Irvine, Ca 92618 Timing: Fiscal Year 2003; Project Start 15-JUL-2003; Project End 14-JAN-2004 Summary: (provided by applicant): The brain damage that frequently accompanies cardiac arrest and resuscitation is devastating. Fewer than 10% of cardiopulmonary resuscitation (CPR) attempts result in survival without brain damage when treatment occurs in pre-hospital or a non-special care hospital environment (Safar, 1993). We propose that a novel vascular-compartmentalized nitroxide, polynitroxyl albumin (PNA), which is an enzyme-mimic antioxidant, can reduce brain damage after CPR. We present preliminary results in a CPR model showing PNA attenuates CA1 hippocampal cell loss 7 days after cardiac compression and resuscitation in rats. Published results also

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support this premise. In a middle cerebral artery occlusion model of stroke, mice treated with PNA were significantly protected against neural damage. We propose to further establish the cerebral protective activity of PNA in a cardiac compression model of CPR. Our specific aims are: 1) to address quality assurance issues in PNA production and in vitro documentation of efficacy, and 2) to compare the impact of PNA, human serum albumin (HSA) and saline treatment on the structure and function of the hippocampus. The end-points for the second aim will include measures of pyramidal cell viability, NMDA receptor 1 immunoreactivity, and in vitro electrophysiology of hippocampal slices. This combined morphological and electrophysiological approach in a whole body ischemia model should further document the value of PNA as a potent neuroprotectant. Attainment of these goals will fulfill the feasibility requirement for further study of PNA in a Phase II SBIR grant, which will emphasize dose response, extended time course, neurological recovery and the therapeutic index of PNA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BRAIN TISSUE RESOURCE CENTRE FOR ALCOHOL RESEARCH Principal Investigator & Institution: Harper, Clive G.; University of Sydney Main Quadrangle, Bld A14 Sydney, 2006 Timing: Fiscal Year 2003; Project Start 01-SEP-2000; Project End 31-AUG-2008 Summary: (provided by applicant): Alcohol-related disorders of the nervous system are major public health and socio-economic problems throughout the world. Per capita consumption of alcohol in Australia is extremely high and, as a result, alcohol-related brain damage is common. A resource (brain bank) to provide these tissues to researchers has been developed in the Department of Pathology at the University of Sydney. The aim of this important and innovative facility, the New South Wales Tissue Resource Center (TRC), is to provide fresh-frozen (-80C) and/or formalin fixed tissues to research groups throughout the world who are studying these disorders. The development of new technologies in pathology and molecular biology means that many more questions can be addressed using appropriately stored human brain tissues. Quantitative neuropathological, neurochemical, neuropharmacological and even neuroimaging techniques can be applied to these tissues. It is possible to detect and measure protein and chemical changes in the brain and abnormalities in gene expression can be identified by the detection and analysis of mRNA molecules. Recent international scientific progress in alcohol-related brain damage attest to the success of the use of these techniques using autopsy tissues. Studies might include dependence and tolerance issues, genetic aspects of alcoholism and mechanisms underlying structural changes in the brain. The accuracy and reliability of the case characterization is paramount to the success of the research projects and reliability of data. Detailed protocols are in place to ensure this outcome. To obtain more cases with full life-style and medical histories a brain donor program called "Using our Brains" (donors sign up during life) has been launched to link with the TRC. A brain bank is necessarily a long-term project and maximum benefits will be seen as case numbers increase. Using the same case material and applying different scientific techniques, research groups can generate data that can be related to pre-mortem clinical, laboratory and radiological information. Funding is sought to help further develop this important resource for international researchers with an interest in alcohol-related brain damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CASPASE MEDIATED CELL DEATH AFTER BRAIN TRAUMA Principal Investigator & Institution: Raghupathi, Ramesh; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2003 Summary: (provided by applicant): Traumatic brain injury (TBI) is the leading cause of death among individuals under the age of 45 in the United States and survivors are faced with chronic brain damage leading to debilitating behavioral dysfunction. Brain damage and behavioral dysfunction may be, in part, due to neuronal death following TBI. The hypothesis to be tested in this proposal is that post-traumatic neuronal cell death is a result of activation of the pro-apoptotic caspase family of cysteine proteases. The objectives of this proposal are to elucidate (1) the association between neuronal death in experimental TBI and in postmortem tissue from head-injured patients and the activation of the "executor" caspase-3, (2) whether caspase-3 activation occurs directly as a result of activation of the "initiator" caspase-8, and/or indirectly as a result of mitochondrial pathway which requires Bax translocation, cytochrome c release and caspase-9 activation, (3) whether caspase-8 activation occurs as a result of activation of the tumor necrosis factor family of death receptors, (4) the role of Bax in mediating trauma-induced caspase-9 activation and subsequent caspase-3 activation and cell death, and (5) whether post-traumatic inhibition of caspases-3, -8 and -9 will reduce the extent of injury-induced cell death. Immunoblot and immunohistochemical analyses using specific and selective antibodies will be utilized to temporal and regional patterns of activation of caspases-3, -8 and -9, resdistribution of Bax and cytochrome c, and, apoptotic neuronal damage, as indicated by the presence of cellular DNA fragmentation and morphologic analyses. Mice deficient in TNF will be used to determine the role of TNF in mediating activation of caspases-8 and -3, and eventual apoptotic cell death by using immunoblot, immunohistochemical and histological analyses. The role of Bax in trauma-induced activation of caspase-9 and -3, cytochrome c redistribution, apoptotic neuronal death and behavioral dysfunction will be examined using immunoblot and immunohistochemical techniques, and by testing cognitive and motor function in braininjured, Bax-deficient mice, followed by histological analysis of cell death. The effect of post-traumatic treatment with peptide inhibitors selective for caspases-3 (DEVD), -8 (IETD) and -9 (LEHD), on the extent of regional cell death and behavioral dysfunction will provide the mechanistic link between caspase activation and TBI-induced pathology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CEREBRAL OXYGENERATION DURING CARDIOPULMONARY BYPASS Principal Investigator & Institution: Jonas, Richard A.; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2001; Project Start 15-JUL-1998; Project End 31-MAY-2005 Summary: (Provided by Applicant): Brain damage including focal and global cerebral injury as well as suboptimal cognitive developmental outcome continue to be important problems after pediatric heart surgery. Previous work in this area has focused on deep hypothermic circulatory arrest (DHCA) which is now used infrequently. As an alternative to DHCA reduced flow hypothermic cardiopulmonary bypass (CPB) is employed. However in the absence of a validated method for real time monitoring of brain oxygenation there are no guidelines for minimal safe flow and pressure under specific CPB conditions of pH, hematocrit and temperature. The proposed study will

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employ the new techniques of near infrared spectroscopy (NIRS) and intravital microscopy (IVM) to defme a minimal safe flow rate for specific perfusion conditions. The study will be conducted using a juvenile piglet model exposed to various degrees of flow reduction with survival for 4 days postoperatively. Survival allows assessment of functional evidence of brain injury through behavioral assessment by a blinded veterinarian observer as well as meaningful histology determined by a blinded neuropathologist. These functional and structural endpoints will be correlated with indices of brain oxygenation measured by NIRS (Tissue Oxygenation Index (TOl), Oxyhemoglobin nadir time (Hb02 nadir time)) as well as indices of microvascular perfusion measured by IVM (functional capillary density (FCD), NADH fluorescence). The second phase of the proposed study will test the hypothesis that critically reduced low flow perfusion causes hypoxic endothelial injury of cerebral blood vessels. This results in reduced constitutive endothelial nitric oxide synthase (eNOS) activity resulting in microvascular regional ischemia previously described as the "no reflow phenomenon." Acute studies will be undertaken in the piglet model using Western immunoblotting and immunocytochemistry as well as resistance vessel myography to measure eNOS activity. eNOS activity will be manipulated by substrate enhancement and inhibition. The role of inducible NOS (iNOS) in causing neurotoxicity in this setting will also be explored. The proposed study has the potential to reduce the risk of brain injury in children undergoing heart surgery by defining the margin of safety achieved with various perfusion conditions. By enhancing understanding of mechanisms of cardiopulmonary bypass-related brain injury it will facilitate development of novel pharmacologic methods to further reduce the risk of brain damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CEREBROVASCULAR EFFECTS OF PRENATAL ALCOHOL Principal Investigator & Institution: Gleason, Christine A.; Professor and Head; Pediatrics; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAY-2005 Summary: (adapted from applicant's abstract) Fetal brain damage resulting from maternal alcohol abuse is one of the leading causes of mental retardation in the United States and yet the mechanisms by which in utero alcohol exposure adversely affects fetal brain development and function are largely unknown. The investigators have recently demonstrated attenuated hypoxic; cerebral vasodilation in newborn sheep which were exposed to chronic maternal alcohol intoxication in the first trimester. Based on these and other supportive findings, they have developed the hypothesis that in utero alcohol exposure affects the development and function of cerebral blood vessels, and that the consequent vascular abnormalities may contribute to the pathogenesis of brain damage associated with fetal alcohol exposure. The objective of this proposal is to further characterize the cerebrovascular and neuropathological effects of chronic fetal alcohol exposure in sheep, and to evaluate potential mechanisms for and consequences of these effects. They will use in vivo and in vitro physiological methods as well as neuropathology and immunocytochemistry to address the following aims: Aim #1: To determine whether chronic maternal alcohol intoxication in the first or second trimester alters fetal cerebrovascular responses to hypoxia in vivo later in pregnancy. Aim #2: To compare the neuropathologic effects of repeated hypoxic insults in fetuses previously exposed to either alcohol or saline in utero. Aim #3: To determine mechanisms whereby prenatal alcohol exposure alters cerebrovascular reactivity by examining the maturation of the cerebral vascular network and by studying the density and expression of cerebral vasodilatory substances. Aim #4: To determine whether prenatal alcohol alters

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cerebrovascular reactivity in vitro by testing the responses of cannulated, pressurized fetal and adult sheep arterioles to vasoactive substances. Aim #5: To determine whether prior prenatal alcohol exposure during pregnancy alters fetal or adult cerebrovascular responses to acute alcohol intoxication. Results from these studies will provide important new information regarding the contribution of fetal cerebrovascular abnormalities to the brain damage associated with fetal alcohol exposure and will lead to the development of perinatal preventive and/or therapeutic strategies for pregnant women who use alcohol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHANGES IN ADDICTIVE BEHAVIORS AFTER BRAIN LESIONS Principal Investigator & Institution: Bechara, Antoine; Assistant Professor; Neurology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): An R21 for CEBRA: The blossoming field of functional neuroimaging studies has pointed to a network of neural structures that subserve the cognitive and behavioral processes of drug addiction, including nicotine. This neural network includes the orbitofrontal cortex, anterior cingulate, insular cortices, the amygdala, and the striatum (dorsal and ventral (nucleus accumbens) striatum). However, no work to date has addressed how damage to different components of this neural network in humans may impact the craving, subjective feeling of drug administration, and active seeking of drugs. Nor any study has asked which, if any, of these components is critically necessary for maintaining the addiction to drugs. This proposal will take advantage of our unique University of Iowa Department of Neurology Patient Registry to begin addressing some of these important issues in patients addicted to cigarette smoking. Our goal is to understand how focal lesions in brain areas hypothesized to be critical neural substrates for addiction affect cigarette smoking behavior, cue-induced craving and smoking urge, as well as the acute subjective effects of smoking. The studies we propose here seek to address 3 specific aims: (1) determining the real-life changes in smoking behavior, cigarette craving, and smoking satisfaction after the onset of brain damage; (2) determining in laboratory experiments the effects of focal brain lesions on (a) the emotional reactivity to smoking cues, (b) the subjective feeling of craving and urge to smoke, and (c) the subjective feeling of smoking a cigarette; and (3) establishing a Registry of neurological patients pre-morbidly known to abuse other substances, including alcohol, stimulants, and opiates, so that they will participate in future research on addiction to drugs. The proposal is promising because (1) it provides a novel perspective for looking at the neurobiological basis of addiction, which compliments and validates the ongoing work with functional neuroimaging techniques; (2) it may help us identify specific brain regions, which damage (or dysfunction) can effectively break the cycle of addiction. The proposed studies are feasible because of (1) our access to the patient population and resources necessary for the conduction of this type research; 2) the guidance of our investigations by an established theoretical framework, the somatic marker hypothesis, and by abundance of background evidence from functional neuroimaging studies. Thus, the proposed research is a beginning of a novel approach with potential for developing more effective therapies for breaking the vicious cycle of addiction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC CORRELATES

ALCOHOL

17

CONSUMPTION--NEUROBIOLOGICAL

Principal Investigator & Institution: Walker, Don W.; Professor; Neuroscience; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2002; Project Start 01-JUL-1978; Project End 31-OCT-2002 Summary: Chronic ethanol consumption produces brain damage manifested by morphological, physiological, biochemical and cognitive abnormalities. Controlled studies in laboratory animals have provided convincing evidence of the specificity of ethanol in inducing these abnormalities, however neither the mechanism of ethanol toxicity nor the specific morphological or functional basis of ethanol induced cognitive deficits are known. Considerable evidence has demonstrated that chronic ethanol treatment (CET) results in significant loss of hippocampal neurons, altered dendritic structure and function of surviving neurons and loss or rearrangement of synaptic connections. Damage to the septohippocampal pathway is implicated in deficient memory and learning and this has been attributed to cholinergic deafferentation of the hippocampus, although the role of GABAergic projections has not been carefully examined. Recently it has been reported that CET produces a progressive decline in spatial memory, cholinergic function and acetylcholinesterase-positive neurons in the septal area. If confirmed, these findings represent an important link in our understanding of the morphological and functional basis for the memory deficits found in alcoholism. The proposed work will attempt to confirm and extend these results to include studies of cholinergic and GABAergic morphology and function in the septa] area and the hippocampus. We will investigate the hypothesis that the septohippocampal pathway is particularly vulnerable to CET. Since septohippocampal neurons are dependent on trophic factors for survival and maintenance of their function, we will also investigate the hypothesis that their vulnerability to CET is mediated by the suppression of neurotrophic influence. The first series of experiments will use immunohistochemical, biochemical and electrophysiological techniques to examine the effects of CET on the morphology and function of the septohippocampal pathway. Both cholinergic and GABAergic septohippocampal neurons in the septal area and their target neurons (principal cells and interneurons) in the hippocampus will be studied. The second series of experiments will test the hypothesis that the vulnerability of the septohippocampal system to CET is mediated by the suppression of neurotrophic influences. Tissue culture bioassay and ELISA methods will be used to determine if CET produces a decrease in the content or bioactivity of neurotrophic factors in the hippocampus and/or if acute ethanol exposure attenuates or blocks the action of neurotrophic factors. Immunohistochemical methods will be used to determine if CET reduces the number of septohippocampal neurons immunoreactive for neurotrophic factor receptors, thus further limiting the availability of neurotrophic influence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COGNITIVE & BEHAVIORAL CONSEQUENCES OF FOCAL BRAIN LESIONS Principal Investigator & Institution: Anderson, Steven W.; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002 Summary: Little is known regarding the effects of damage to specific regions of the human brain when this damage occurs early in life, although there is reason to believe that certain impairments of cognition and behavior are a consequence of early-onset

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Brain Damage

brain damage. The NINDS has identified as high research priorities the gathering of more precise descriptions of behavior patterns and developmental disorders, and the achievement of greater understanding of the neural basis of cognition, emotion, and their interaction. Lesion method studies of individuals who have sustained early-onset focal brain damage are an important means to fulfill such priorities, and during the current funding period we have conducted pilot studies of adults with early-onset focal brain damage and marked cognitive and behavioral impairments. Conditions causing focal brain damage in childhood are not common, but a sufficient number of patients is now available for systematic studies. Here we propose to establish a registry of patients with damage to circumscribed brain regions acquired during development, namely during the perinatal period, infancy, childhood, or adolescence, and to perform hypothesis-driven studies of these individuals using: (1) precise description of brain lesions using MRI with 3-D reconstruction, (2) comprehensive characterization of cognition and behavior with standardized, age-appropriate neuropsychological measures, (3) standardized indices of functional outcome (academic achievement, employment, quality of life, and family burden), and (4) experimental measures of cognition and behavior, with a focus on emotion, moral reasoning and social competence Delineation of relationships between damage to specific neural systems early in life and the short- and long-term consequences for cognition and behavior should provide fundamental information which will be relevant to the understanding of human development, and permit better evaluation and treatment of treatment of neurobehavioral disorders with onset in childhood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COGNITIVE NEUROSCIENCE OF DEMENTIA Principal Investigator & Institution: Farah, Martha J.; Professor; Psychology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 15-SEP-1997; Project End 31-AUG-2003 Summary: After 10 years as a PI in research on cognitive impairments following stroke, and some recent preliminary work on cognition in AIzheimer's disease (AD), l have decided to turn my attention more fully towards the dementias. Although cognitive neuroscience has generally concentrated on focal brain damage, I believe that AD and other dementias, including Parkinson's disease, Huntington's disease and semantic dementia, have much to teach us about the functioning of the normal mind and its neural substrates, particularly with respect to semantic memory and visual cognition, my two areas of specialization. In addition, the dementias represent a major public health problem, and the cognitive neuroscience approach may be able to contribute towards solutions to this problem. I am therefore requesting support to undertake five years of study, research, and career development in the cognitive neuroscience of dementia. During this period I will carry out the proposed research on semantic memory and visual cognition in AD while learning more about AD and other dementias. My goal is to become as competent in research on dementia as I am now in research on focal brain damage, and thereby to contribute to our basic-science understanding of the dementias and to advances in the diagnosis and management of these diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPREHENSION IMPAIRMENT AND RIGHT BRAIN DAMAGE Principal Investigator & Institution: Tompkins, Connie A.; Professor; Communications; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260

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Timing: Fiscal Year 2003; Project Start 01-SEP-1993; Project End 30-NOV-2006 Summary: (provided by applicant): The proposed research aims to improve our understanding of discourse comprehension deficits often incurred by adults with right hemisphere brain damage (RHD) as a result of stroke. Among the most prominent impairments in this population is a difficulty comprehending material that supports or induces multiple, ostensibly competing interpretations. While these deficits can be quite socially handicapping, they are poorly understood, with conflicting explanations the rule. Two groups of adults, 50 with RHD and 45 without brain damage, will complete auditory sentence- and discourse-level comprehension tasks. Tasks will be designed to generate less explicit and more sensitive than usual indices of comprehension. One main goal of the proposed work is to test the Pl's 'suppression deficit' view of typical RHD deficits in comprehending material that supports competing interpretations, against influential theoretical alternatives in the lexical-semantic processing and social cognition domains. The proposal aims to (1) resolve conflicting hypotheses (suppression deficit vs. maintenance deficit) about RHD lexical-semantic deficits when processing sentences that contain words with alternative meanings or features; (2) test the claim of both the suppression and maintenance deficit positions that such word-level deficits will predict typical RHD discourse comprehension deficits; (3) test the hypothesis that RHD suppression deficits also will predict 'presumed' social cognition impairments (i.e., 'theory of mind' (TOM) deficits), as inferred from common discourse assessment tasks; (4) challenge the validity of the TOM-deficit attribution for RHD comprehension impairments, given various confounds in common TOM assessments; (5) test specific hypotheses about neuroanatomic bases of possible RHD lexical-processing and TOM deficits; (6) assess whether competing proposals can be reconciled with reference to within-hemisphere lesion location; and (7) evaluate the within domain generality of results with the same large sample of RHD adults, using multiple measures of word and discourse-level deficits. The results of the proposed investigations will advance theorizing in a nascent area of investigation and, by bolstering theoretical rationales for assessment and treatment, have eventual clinical implications for this understudied population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTRASTING TREATMENT FOR SENTENCE PRODUCTION DEFICITS Principal Investigator & Institution: Maher, Lynn M.; Associate Professor; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001 Summary: The syndrome of agrammatism is a form of language impairment that affects sentence processing and results from acquired brain damage. Treatment studies which have taken the complexity of the underlying system into account have demonstrated improvements in sentence processing. What has not been determined is how the underlying physiology of the recovering system effects or interacts with this type of intervention. Furthermore, while there is a developing body of evidence to suggest that learning environments which encourage accurate responses and prevent error responses (i.e. errorless learning) are more efficacious than traditional models of errorful learning, there has been minimal application of this learning theory towards the rehabilitation of acquired brain damage, except in the area of memory (Wilson et al., 1994). The purpose of this subproject is to apply recent advances in learning theory and cognitive linguistics to the rehabilitation of the sentence production deficits observed in this syndrome. We will test the application of errorless learning, an approach supported by parallel

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distributed models of learning and cognition, to the rehabilitation of sentence production deficits. We will do this by comparing the effectiveness of this approach so that of more traditional, errorful learning. Furthermore, we will compare the impact of vicariative substitutive treatment method (i.e. one designed to encourage alternative processes to assume damaged functions) that is derived from current cognitive linguistic models of sentence production, with a restitutive approach (i.e. designed to restore function) that is more typical of traditional aphasia therapy. In so doing we can address the relative limitations of the underlying physiology of the damaged system since current therapies of brain repair suggest that the potential for recovery of function may be time-dependent. By comparing errorless and errorful learning strategies and their interactions with substitutive versus restitutive treatment approaches in a single subject design, we may identify rehabilitation environments which can maximize the individual's response to rehabilitation. It is also the goal of this project to determine if improvements observed in the controlled rehabilitation environment generalize and have an effect on the individual's functional ability to communicate. Generalized improvement in sentence production would contribute to greater independence and improved quality of life. Finally, we will attempt to associate functional changes in sentence production as a result of rehabilitation with observable changes in neural activity using fMRI. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROLLED REPERFUSION FOR WHOLE BODY ISCHEMIC INJURY Principal Investigator & Institution: Buckberg, Gerald D.; Surgery; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The long-term objective is to develop a new approach to treat cardiac arrest. Currently, despite early, successful defibrillation in half the patients, the overall mortality rate is 95%. Furthermore, approximately 70% of these few survivors of whole body ischemia develop neurologic injury: we may save the heart, but lose the brain. The causative factors are inadequate treatment of the underlying cause of arrest by insufficient a) delivery of brain flow during CPR, b) restoring of heart blood supply to allow it to recover, and c) correction of the underlying cardiac cause. A novel approach will be taken to 1) promptly use the heart lung machine without opening the chest by an approach through leg vessels to mechanically, and temporarily, take over heart function, 2) change its prime pharmacologically to make a metabolic fuel for recovery, and 3) correct the underlying cause. We will use a relevant surgical model of either deep hypothermic circulatory arrest (DHCA) or lethal normothermic ventricular fibrillation for 10 minutes to cause whole body ischemia. Both insults cause high mortality and brain damage. We will present pilot studies showing complete heart and 100% brain recovery by integrating the specific aims of these three interventions. These results were achieved by use of a standard prime of the CPB circuit, and adding either a sodium hydrogen exchange inhibitor or specially filtering the white blood cells that cause reperfusion damage. We will extend the period of ischemia to two hours and show how this cardiac arrest model (that permits regional brain flow through the carotid arteries) can also be used to treat stroke. If this novel method of management is correct, the scheme of diagnosis and management of this almost always fatal cardiac arrest complex will change markedly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENT OF COGNITIVE FUNCTIONS: FRONTAL LOBE Principal Investigator & Institution: Diamond, Adele D.; Director; Eunice Kennedy Shriver Center; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, Ma 01655 Timing: Fiscal Year 2001; Project Start 10-JUN-1997; Project End 31-MAY-2003 Summary: The goals of the proposed research are three:(1) to test children with brain damage localized to frontal cortex on tests (a) which have been linked specifically to frontal cortex function through neuroanatomical and behavioral studies with infant and adult monkeys and (b) on which we know the normal developmental progression in children. Important aspects of this work will be to look for converging evidence from diverse tests all linked to the same subregion of frontal cortex, and to attempt to dissociate performance on these tests from performance on tests linked to other neural circuits. The goal is to develop non-invasive tests capable of detecting frontal cortex damage in infants and young children. Presently such damage often goes undetected for many years because of the lack of such tests. (2) to investigate the relationship of dopamine levels to performance on these tasks, and to begin to investigate the hypothesis that the fundamental maturational change which underlies the emergence of cognitive abilities dependent on frontal cortex during infancy is increasing levels of frontal cortex dopamine. To do this, children with early-treated PKU, who have no known structural brain damage but who are vulnerable to reduced levels of dopamine will be tested. Because their general cognitive functioning is good, if deficits are found they are likely to be selective. If they are selectively impaired on tests of frontal cortex function, this will be the first demonstration in humans of a cognitive deficit on frontal cortex tasks from dopamine depletion alone. Because L-dopa and the dopamine precursor, tyrosine, can be taken orally, there is an excellent chance that if deficits are found, therapeutic interventions will be possible to alleviate any impairments. (3) to better understand the abilities required for success on tasks that depend on frontal cortex function. Hypotheses will be considered that suggest that memory for space, and/or time, or for relational information in general is dissociable from memory for other information and dependent upon frontal cortex function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEVELOPMENTAL BRAIN DAMAGE BY DRUGS OF ABUSE Principal Investigator & Institution: Olney, John W.; Professor; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2001; Project Start 01-SEP-1994; Project End 31-JAN-2005 Summary: (adapted from applicant's abstract)This is an application for competing renewal of a grant that was funded for five years (1994-1999) and was devoted to an investigation of neurotoxic damage induced in the adult rodent brain by phencyclidine (PCP) and related drugs that block NMDA (N-methyl-D-aspartate) glutamate (Glu) receptors. During the grant period, the applicants developed significant new insight into the mechanism of this adult brain damage syndrome and into the potential relevance of this mechanism to human neuropsychiatric disorders. In the course of this work, it was discovered that the immature brain is not vulnerable to damage by this mechanism, but that NMDA antagonists, including PCP and ketamine (both of which are drugs of abuse), can induce an extensive pattern of permanent damage in the developing rat brain by an entirely different mechanism. As a tool for studying this mechanism we have primarily used MK801, a powerful NMDA antagonist that binds with high affinity to the PCP recognition site in the NMDA receptor ion channel. Our interpretation of the

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mechanism, based primarily on MK801 studies, is that immature neurons during a specific stage in development (the synaptogenesis stage, also known as the brain 'growth spurt' stage) are intrinsically dependent on NMDA receptor stimulation for survival, and they are programmed to commit suicide (die by apoptosis) if deprived of this receptor input for several consecutive hours during this critical period. The objectives of this renewal application are to further characterize the ability of several drugs of abuse to trigger apoptotic neurodegeneration in the developing mammalian brain, and evaluate the potential relevance of this neurodegenerative phenomenon to human neurodevelopmental disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIETARY RESTRICTION, AGING, LEARNING, AND LTP Principal Investigator & Institution: Barea-Rodriguez, Edwin J.; University of Texas San Antonio San Antonio, Tx 78249 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: The oxidative stress theory of aging states that damage to molecules that are important for cellular function increases with age. This increase causes a decline in normal physiological function in a number of organs including the brain. Normal aging may be accompanied by a decline in cognitive function. It is widely believed that learning and memory are mediated by dynamic changes in the brain. Long-term potentiation (LTP) is an activity-dependent form of synaptic plasticity thought to be to be the most plausible mechanism for learning and memory. LTP was first discovered in the hippocampus, a neural structure associated with learning and memory. Interestingly, aging is accompanied by impairments in both hippocampal-dependent learning and LTP. Dietary restriction (DR) is the only environmental manipulation known to extend lifespan in all mammals studied. Many studies report that DR can prevent age-related impairments in hippocampal-dependent learning tasks. Most DR studies implement a life-long DR regimen and the animals used are adults at the time of testing. Few studies investigate the effects of short-term DR in aged rats and its consequences for learning and memory. Also, the relationship between DR and LTP longevity remains largely unexplored and no current studies document the effects of short-term DR on LTP in aged rats. The long-term goal of this research is to investigate age-related increases in oxidative brain damage, age-related deficits in hippocampaldependent learning and medial perforant path (MPP)-CA3 LTP in awake rats, as well as their prevention by short-term (3 months) DR. In Specific Aim 1, experiments will investigate whether short-term DR can improve the performance of aged rats in trace fear conditioning and the Morris Water Maze. In Specific Aim 2, experiments will investigate whether short-term DR can extend LTP longevity in aged rats. In Specific Aim 3, experiments will investigate whether short-term DR decreases levels of oxidative brain damage and increases levels of the neuroprotective brain proteins Heat Shock Protein 70 and Brain Derived Neurotrophic Factor. These studies are expected to increase our understanding of how oxidative damage impairs hippocampal-dependent learning and LTP, how such impairments can be prevented by dietary manipulations, and whether the proposed molecular mechanisms are associated with such improvements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DIFFUSE BRAIN ABNORMALITY IN SICKLE CELL DISEASE Principal Investigator & Institution: Steen, R Grant.; St. Jude Children's Research Hospital Memphis, Tn 381052794

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Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 31-MAY-2003 Summary: Sickle cell disease (SCD) is the most common hemoglobin mutation in the US, affecting 60,000 people. SCD is often associated with focal brain abnormalities that worsen as the disease progresses, and conventional MRI (cMRI) can demonstrate focal damage even in infants. At least 1 in 4 SCD patients show cMRI evidence of focal abnormality by age 20. However, we hypothesize that diffuse brain abnormality is actually more common than focal damage, and that it usually precedes focal damage. Because diffuse abnormality cannot be well-visualized by cMRI methods, the prevalence of diffuse abnormality is not known. Our goal is to determine whether new quantitative MRI (qMRI) methods are more sensitive than cMRI methods to diffuse brain damage in SCD patients, and to ascertain whether diffuse brain abnormality correlates with the clinical course of disease. We will use qMRI methods developed in our lab, in a prospective, longitudinal, clinical study of young SCD patients. We will enroll 50 patients and 50 sibling controls, and follow all enrolled subjects prospectively for 5 years. We will use T1 mapping and quantitative MR angiography (qMRA), to characterize the prevalence and to evaluate the significance of diffuse brain abnormality in pediatric SCD patients. Data from cMRI, qMRI and qMRA will be correlated with clinical and psychometric data, to determine which MR imaging data are predictive of clinical severity or development of cognitive deficits. To be specific, we will: characterize the relationship between diffuse T1 reduction and focal brain abnormality detected by cMRI; determine if diffuse T1 reduction is associated with subtle loss of gray or white matter volume measured by cMRI image segmentation; ascertain if diffuse T1 reduction is correlated with psychometric deficit; and establish whether diffuse T1 reduction is associated with vasculopathy, including ectasia or stenosis of the cranial arteries. Because infarctive stroke risk in young SCD patients is 6-fold higher than in healthy adults, SCD patients may provide a clinical model for the most common type of stroke in elderly adults. We will establish whether these novel qMRI methods provide a sensitive and clinically-relevant indicator of diffuse brain injury. Our long- range goal is to determine the mechanisms causing cognitive loss in SCD patients, in an effort to determine a therapeutic strategy to minimize such damage in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISCOURSE PERFORMANCE AFTER RIGHT BRAIN DAMAGE Principal Investigator & Institution: Brownell, Hiram; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2001 Summary: Naturally occurring communication very often takes the form of discourse such as, for example, a friendly conversation. The success of conversations that serve social as well as informational purposes is largely determined by whether the participants obey the rules governing polite discourse. Inappropriate comments or word choices can divert attention from the literal message and, more importantly, can undermine the social bond between the people speaking. Abiding by these conventions requires understanding what affects the feelings other people, keeping track of what other people know and do not know, and knowing what is appropriate in different discourse settings defined by people's feelings and knowledge. The effects of unilateral brain injury on patients' success with these aspects of discourse. The patients of most interest are those who have sustained right hemisphere brain damage (RHD) due to stroke but who do not have aphasia. Non brain-damaged control subjects will provide the primary comparison group in light o the heavy linguistic demands of most of the proposed tasks, but right and (nonaphasic) left prefrontally damaged patients will be

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tested when possible to provide information on localization of function, as will aphasic LHD patients with middle cerebral artery territory lesions. Results from the planned studies will provide a window onto the mental life of the brain-injured individual and will help. us understand the ways in which brain injury impairs social reasoning which is a major source of difficulty for RHD patients and their families. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF ALCOHOL ABUSE ON THE AGING BRAIN Principal Investigator & Institution: Fein, George; President; Neurobehavioral Research, Inc. Corte Madera, Ca 94925 Timing: Fiscal Year 2001; Project Start 25-SEP-1997; Project End 31-AUG-2005 Summary: (Adapted from the Investigator's Abstract) The primary goal of the proposed research is to test two opposing models of why the CNS morbidity due to alcohol abuse is greatest in the elderly alcoholic. The generally accepted age-related vulnerability model postulates a greater vulnerability of the older brain to the toxic effects of alcohol. An alternative model, the cumulative effects model, postulates the duration and amount of abusive drinking (regardless of when in the lifespan it took place) and the aging process as the only factors underlying the greater CNS morbidity in the older alcoholic. In the cumulative effects model, the younger brain is able to compensate for the damage done by alcohol abuse/dependence until cognitive losses associated with normal aging undermine these compensatory mechanisms and the CNS morbidity due to alcohol abuse/dependence (earlier in life) becomes apparent. There is no data in the literature to test the differential predictions of these models (e.g., data on the CNS status of elderly individuals who were alcoholic into late middle age, but who have been abstinent for 10 years or more) because research to date has focused only on recently abstinent individuals. We will test these two opposing models of how age modulates chronic alcohol abuse effects on CNS structure and function using state-of-the-art methods. Structural brain imaging will be used to assess regional morphological brain changes; electrophysiological and neuropsychological testing will assess functional changes in information processing abilities. The study will use a cross-sectional design with five groups, each group consisting of 30 males and 30 females. The secondary goal of this project is to determine whether there are gender differences in the effects of chronic alcohol abuse on CNS function, and the matter in which age modulates these effects. Our final goal in the project is to examine other factors (e.g., brain "functional reserve," presence of the APOE-epsilon4 allele) that may modulate the effects of chronic alcohol abuse/dependence and age on brain structure and function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENDOTHELIAL PRECONDITIONING AND ISCHEMIC BRAIN INJURY Principal Investigator & Institution: Keep, Richard F.; Associate Professor; Neurosurgery; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2003; Project Start 25-JUL-1996; Project End 31-MAY-2008 Summary: (provided by applicant): Ischemic preconditioning (IPC) has proved to be one of the most effective methods of reducing ischemic brain damage in animal models of stroke. Attention has focused on the mechanisms by which neurons may be protected by such preconditioning. However, we have found that IPC also protects the endothelium, which forms the blood-brain barrier, from ischemic damage. 'Ischemic' preconditioning

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also protects cerebral endothelial cells in vitro from oxygen glucose deprivation induced injury indicating that there can be direct preconditioning of the endothelium. Damage to the cerebral endothelium may potentiate ischemic brain injury in a number of ways and determining mechanisms to reduce endothelial damage is particularly pertinent at the moment considering the role of endothelial injury (hemorrhagic transformation) in limiting the use of tissue plasminogen activator for the treatment of ischemic stroke. We will examine the mechanisms involved in cerebral endothelial preconditioning both in vivo (rat middle cerebral artery occlusion) and in vitro (primary cultures of rat cerebral microvessel endothelial cells). The in vitro experiments will facilitate exploration of the mechanisms involved in preconditioning while assuring that the preconditioning acts directly on the endothelium. The in vivo experiments will ensure that the mechanisms elucidated in vitro also occur in the whole animal as well as allowing an assessment of the effects of preconditioning on other parameters (such as blood flow, capillary morphology and infarction). Overall the proposal has three main goals. 1) Determine the time course of preconditioning and the extent of its effects on the endothelium (Specific Aim 1). 2) Determine the events that can trigger endothelial preconditioning (Specific Aim 2). 3) Determine what mechanisms are triggered to protect the endothelium (Specific Aim 3). These experiments should provide information on: A) Endogenous defense mechanisms that protect the cerebral endothelium from ischemic injury and which may be therapeutic targets. B) The role of endothelial preconditioning in the effects of IPC on the brain. C) The role of endothelial injury in the overall effects of ischemia on the brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENERGY METABOLISM Principal Investigator & Institution: Smith, Michael B.; Chief, Center for Nmr Research; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2002 Summary: The overall objective of this research component is to investigate the highenergy biochemical mechanisms whereby the perinatal brain is damaged by hypoxiaischemia and how brain injury can be prevented or reduced through specific modalities of therapy. Specific Aims include: 1) to characterize the earliest alterations in highenergy phosphate reserves which occur during perinatal cerebral hypoxia-ischemia and to correlate these changes with perturbations in cerebral energy utilization, cerebral glucose utilization, glutamate and nitric oxide neurotoxicity, and intracellular calcium accumulation; 2) to correlate the concentrations in cerebral high-energy phosphate reserves and the changes which occur during hypoxia-ischemia using 31P magnetic resonance (MR) spectroscopic methods and enzymatic, fluorometric techniques; 3) to characterize the secondary (delayed) energy failure which occurs during recovery from perinatal cerebral hypoxia-ischemia and to correlate the alterations with the presence and severity of hypoxia-ischemic brain damage; 4) to ascertain underlying biochemical mechanisms whereby the glucocorticosteroid, dexamethasone, protects the perinatal brain from hypoxic-ischemic damage; 5) to determine the protective influence of magnesium sulfate on perinatal hypoxic-ischemic brain damage and, if so, to ascertain its mechanism of action; and 6) to investigate further the presence and extend of alterations in diffusion-weighted and T2-weighted imaging during recovery from perinatal cerebral hypoxia-ischemia and to correlate any changes with the nature and extent of cerebral edema and associated neuropathologic alterations. Seven-days postnatal rats will undergo unilateral cerebral hypoxia-ischemia, during and following which the animals will undergo those procedures necessary to obtain sequential 31P and

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1H NMR spectra which will allow for measurements of the alterations in high-energy phosphate reserves and other metabolites which result from the insult. Other animals will undergo MR imaging at specific intervals following cerebral hypoxia-ischemia. Other experiments will elucidate the neuroprotective effect of dexamethasone, magnesium sulfate, and L-NAME on hypoxic-ischemic brain damage in the developing rat. Analytic procedures will include sequential measures with NMR spectroscopy as well as brain tissue analysis of high-energy phosphate reserves and other metabolites using enzymatic, fluorometric techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ETIOLOGY OF CELLULAR DAMAGE AFTER EXPERIMENTAL STROKE Principal Investigator & Institution: Aronowski, Jaroslaw A.; Associate Professor; Neurology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2001; Project Start 01-AUG-2001; Project End 31-JUL-2006 Summary: The objective of this proposal is to examine the relationship of the transcription factor nuclear factor-kappaB (NF-kappaB), and its activation pathway, to neuronal damage induced by intracerebral hemorrhage. The experiments proposed are largely based upon preliminary data linking cellular death to NF-kappaB activation after cerebral infarction and hemorrhage, and our recent finding of involvement of a novel enzyme in the NF-kappaB regulatory pathway, inhibitor kappaB-kinase (IKK). Our overall hypothesis is that the acute phase response following cerebral hemorrhage is in part a dynamic inflammatory response coordinated at the gene transcription level. We hypothesize that NF-kappaB activation leads to neuronal death that is controlled upstream by the phosphorylation of inhibitor kappaB (IkappaB) by IKK. We propose two specific aims. First using carefully selected pharmacologic (15d-PGJ2, IKK inhibiting peptide and proteasome inhibitor) and molecular (knockout and transgenic mice) probes, affecting important components of the NF-kappaB transduction pathway at different up-stream levels of its activation, we will determine the causal relationship of the NF-kappaB pathway to brain damage (neuronal loss and behavioral dysfunction) after intracerebral hemorrhage. Next using relevant biochemical, microscopic and molecular techniques and brains from animals that benefited from inhibition of upstream components of NF-kappaB activation, we will describe the temporal and spatial characteristics of this inhibition and pin down the exact components of the pathway down-stream from the inhibition site, including IKK activity, IkappaB-phosphorylation, NF-kappaB DNA binding and NF-kappaB gene transactivation that were affected by these inhibitions. Subsequently, using a single cell level analysis we will identify what cell type(s) represent the primary target of anti-NF-kappaB therapy in treatment of ICH. These laboratory studies in animal models of hemorrhage and infarction will provide the framework for developing a possible new approach to therapy for stroke in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EXACERBATION OF ALZHEIMER'S DISEASE BY NITROUS OXIDE Principal Investigator & Institution: Kofke, W Andrew.; Anesthesia; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2004 Summary: Research Topic: 3. Alzheimer's Disease Drug Discovery. Recent clinical reports indicate that the onset of Alzheimer's disease (AD) is earlier with prior mild neurologic insults or with increasing prior anesthetic exposure. The specific

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characteristics of anesthesia history that predispose to this earlier onset of AD are unknown but such observations raise the concern that something about anesthesia may constitute a mild neurologic insult. NMDA antagonists such as nitrous oxide (N20) and MK801 have been demonstrated to have a bimodal dose-related protective and then neurotoxic effect in normal rodents, with congruent regional activation by N20 reported in humans. There is ample data indicating an important role for neuroexcitation with associated oxidative injury in the pathogenesis of AD. It thus becomes reasonable to suggest an interaction between the genesis of AD and prior N20 exposure. Clinically N20 is an extremely common anesthetic with virtually ubiquitousexposure by almost everyone at some point in life. This makes its use a reasonable and potentially immensely important area to explore in the pathogenesis of AD. We hypothesize that N20 exposure has a bimodal dose-related effect to either attenuate or exacerbate subsequently developed AD. We will test the specific hypotheses that: 1. High dose N20 exposure exacerbates cognitive dysfunction and brain damage with AD. In a transgenic model of AD, mice will receive five high-dose exposures to N20 during middle-aged, or elderly ages followed at age 10 months by cognitive assessment, analysis of brain isoprostanes as markers of peroxidation and soluble andinsoluble amyloid, and morphologic assessment for amyloid plaques, apoptosis and neuronal degeneration 2. Low dose repetitive N20 exposure attenuates cognitive dysfunction and brain damage with AD. In a transgenic model of AD, mice will receive low doses of N20 nightly from mid-life to elderly ages, followed at age 10 months by cognitive assessment, analysis of brain isoprostanes and soluble and insoluble amyloid, and morphologic assessment for amyloid plaques, apoptosis and neuronal degeneration. Anesthesia has been implicated in postoperative cognitive dysfunction (POCD) in the elderly and has been impugned in the early onset of AD. The proposed research will explore the potential contribution of a ubiquitous anesthetic with neuroexcitatory side effects in a relevant murine model of AD. This will contribute to a focussed evaluation of the potential causes of POCD the results of which will change the practice of anesthesia and thus significantly attenuate the incidence of POCD in the elderly and possibly impact on the epidemiology of AIzheimer's disease. Moreover, observation of a protective effect may result in discovery of an easily implemented preventative drug therapy for AD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FETAL BRAIN INJURY FROM OXIDANTS FOLLOWING ACUTE HYPOXIA Principal Investigator & Institution: Tan, Sidhartha; Evanston Hospital Evanston, Il 60201 Timing: Fiscal Year 2001; Project Start 01-JAN-1997; Project End 31-DEC-2002 Summary: Irreversible brain damage to the fetus frequently results from prolonged ischemia/hypoxia during pregnancy. Oxidants produced during ischemia- reperfusion can cause significant tissue damage if they overwhelm the body's antioxidant defenses. Pro-oxidant systems, like xanthine oxidase, develop earlier than antioxidant enzyme systems in the developing fetus. The hypothesis of this proposal is that oxidants derived from xanthine oxidase and nitric oxide are responsible for cortical fetal brain damage following acute hypoxia. The hypothesis will be tested using specific inhibitors to xanthine oxidase and nitric oxide generating systems in a preterm gestation rabbit model of acute fetal hypoxia. It is proposed: 1) to determine the involvement of xanthine oxidase in excess oxidant production, depletion of antioxidant defense systems, and brain injury following fetal hypoxia-reoxygenation. It is postulated that xanthine oxidase released into the circulation causes multi-system injury, including brain injury.

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The imbalance between oxidant production and antioxidant systems and the relationship to tissue injury will be investigated following interference with xanthine oxidase activity and administration of antioxidants. 2) to determine the involvement of nitric oxide in excess oxidant production, depletion of antioxidant defense systems, and brain injury following fetal hypoxia-reoxygenation. The interaction of nitric oxide with oxidants, including those derived from xanthine oxidase, will be investigated in fetal rabbits in vivo and in fetal neuronal and astrocyte cultures. The regulation of gene expression of xanthine oxidase, nitric oxide synthase (the enzyme that produces nitric oxide) and superoxide dismutase (a key antioxidant enzyme), and correlation with their enzymatic activity will be determine following acute hypoxia. Completion of the proposed research will broaden the understanding of basic mechanisms of oxidantmediated fetal brain injury, and identify useful biochemical markers and pharmacological ameliorations of brain injury in fetal hypoxia. The laboratories of the sponsors and consultants provide a fertile atmosphere in which to do the proposed studies. The experience and training in neurobiology and molecular biology that the candidate will gain on completion of this proposal will form a solid framework for a successful investigative career. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FREQUENCY DOMAIN CEREBRAL OXIMETER FOR PEDIATRICS Principal Investigator & Institution: Kurth, Dean C.; Attending Anesthesiologist; Near Infrared Monitoring, Inc. (Nim) 3401 Market St, Ste 140F Philadelphia, Pa 19104 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 29-SEP-2002 Summary: Brain damage from hypoxia-ischemia represents a major health problem in pediatrics. At present, no method exists in clinical care to diagnose cerebral hypoxiaischemia in real-time at the bedside, thereby limiting prevention and treatment of the brain damage. Near infrared spectroscopy (cerebral oximetry) is an emerging optical technology with the potential to fulfill this role. In previous work, we built a prototype frequency domain near infrared cerebral oximeter and found it measures cerebral O2 saturation accurately. However, before clinicians will use cerebral O2 saturation to diagnose cerebral hypoxia-ischemia, the measure needs to be related to other known measures of hypoxia-ischemia, and the instrument needs to be engineered to the clinical environment. This fast-track proposal will develop a frequency domain near infrared cerebral oximeter to diagnose cerebral hypoxia-ischemia in real-time at the bedside for pediatrics (