BASAL GANGLIA A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
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 2004 by ICON Group International, Inc. Copyright 2004 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., 1960Basal Ganglia: 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: 0-497-00127-6 1. Basal Ganglia-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.
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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 basal ganglia. 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 BASAL GANGLIA ....................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Basal Ganglia ................................................................................ 5 E-Journals: PubMed Central ....................................................................................................... 63 The National Library of Medicine: PubMed ................................................................................ 64 CHAPTER 2. NUTRITION AND BASAL GANGLIA ........................................................................... 109 Overview.................................................................................................................................... 109 Finding Nutrition Studies on Basal Ganglia............................................................................. 109 Federal Resources on Nutrition ................................................................................................. 111 Additional Web Resources ......................................................................................................... 112 CHAPTER 3. ALTERNATIVE MEDICINE AND BASAL GANGLIA..................................................... 113 Overview.................................................................................................................................... 113 National Center for Complementary and Alternative Medicine................................................ 113 Additional Web Resources ......................................................................................................... 117 General References ..................................................................................................................... 118 CHAPTER 4. DISSERTATIONS ON BASAL GANGLIA....................................................................... 119 Overview.................................................................................................................................... 119 Dissertations on Basal Ganglia.................................................................................................. 119 Keeping Current ........................................................................................................................ 120 CHAPTER 5. BOOKS ON BASAL GANGLIA ..................................................................................... 121 Overview.................................................................................................................................... 121 Book Summaries: Federal Agencies............................................................................................ 121 Book Summaries: Online Booksellers......................................................................................... 122 Chapters on Basal Ganglia......................................................................................................... 122 CHAPTER 6. PERIODICALS AND NEWS ON BASAL GANGLIA ....................................................... 125 Overview.................................................................................................................................... 125 News Services and Press Releases.............................................................................................. 125 Academic Periodicals covering Basal Ganglia ........................................................................... 126 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 131 Overview.................................................................................................................................... 131 NIH Guidelines.......................................................................................................................... 131 NIH Databases........................................................................................................................... 133 Other Commercial Databases..................................................................................................... 135 The Genome Project and Basal Ganglia ..................................................................................... 135 APPENDIX B. PATIENT RESOURCES ............................................................................................... 139 Overview.................................................................................................................................... 139 Patient Guideline Sources.......................................................................................................... 139 Finding Associations.................................................................................................................. 142 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 145 Overview.................................................................................................................................... 145 Preparation................................................................................................................................. 145 Finding a Local Medical Library................................................................................................ 145 Medical Libraries in the U.S. and Canada ................................................................................. 145 ONLINE GLOSSARIES................................................................................................................ 151 Online Dictionary Directories ................................................................................................... 151 BASAL GANGLIA DICTIONARY............................................................................................. 153
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INDEX .............................................................................................................................................. 219
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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 basal ganglia 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 basal ganglia, 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 basal ganglia, 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 basal ganglia. 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 basal ganglia, 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 basal ganglia. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON BASAL GANGLIA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on basal ganglia.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and basal ganglia, 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 “basal ganglia” (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: •
Voiding and MRI Analysis of the Brain Source: International Urogynecology Journal. 10(3): 192-199. 1999. Contact: Available from Springer-Verlag New York Inc. 175 Fifth Avenue, New York, NY 10010. (212) 460-1500. Fax (212) 473-6272. Summary: Observations of surgery, angiography, and postmortem studies have indicated that the frontal lobe of the brain is a higher center important in the control of micturition (urination). CT scan and magnetic resonance imaging (MRI) have made it possible to extend these early results. This article reports on a study of imaging in patients with hemispheric and brainstem strokes. In a series of stroke patients, urinary dysfunction was found in 68 percent of these patients with frontal lesions, 20 percent of patients with parietal lesions, 14 percent with temporal lesions, and none of the patients
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who had occipital lobe lesions. With lesions in the frontal lobe, it appears that medial aspects are particularly important in the prefrontal lobe, cigulate gyrus, paracentral lobule, and the orbital area in micturition control. Frontal lobe disease may cause disorders of storage as well as voiding, as shown by urodynamics: detrusor hyperreflexia, detrusor areflexia, uninhibited sphincter relaxation, and unrelaxing sphincter on voiding were found. The authors also make observations about the role of the basal ganglia and pons in micturition control in humans. 6 figures. 47 references. •
Frontal Functions in Normal Aging and the Performance in Purdue Pegboard Test Source: Research and Practice in Alzheimer's Disease. 151-162. 1998. Summary: This article discusses a study that analyzed the relationship between manual motor ability measured with the Purdue Pegboard (PP) and frontal lobe functions in 62 healthy subjects aged 65 to 87. Researchers used a neuropsychological battery to measure the performance in frontal lobe functions; the PP test classified subjects into two different groups. Results showed significant differences between subjects with and without motor difficulties. The group with lower PP scores presents more deficits in performing frontal-lobe associated activities. These results support the hypothesis that dopaminergic basal ganglia dysfunctions may play an important role in frontal lobe deficits associated with normal aging. Other recent findings showed a positive correlation between atrophy in substantia nigra and deficits in PP execution. 2 figures, 2 tables, 52 references (AA-M)
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Psychiatric and behavioral aspects of dementia of the Binswanger type Source: American Journal of Alzheimer's Disease. 173-178. July-August 1998. Summary: This article presents a literature review and case studies to discuss four symptom-clusters associated with Binswanger's disease. The four symptom clusters are late-onset paranoid psychosis, confused state, depression, and a behavioral syndrome of the frontal lobe type. The symptomatology cannot be regarded as mutually exclusive because features may overlap. The symptoms may precede the intellectual deterioration and motor disturbances that are seen with Binswanger's disease. Binswanger's disease, or subacute arteriosclerotic encephalopathy, is characterized by diffuse myelination of the brain's white matter and lacunar lesions in the basal ganglia and brain stem. Clinically it is a dementing illness associated with varied clinical and radiological abnormalities. The clinical features of Binswanger's disease are highly variable and the psychiatric and behavioral manifestations have not been well described. White matter lesions, cortical-cortical, and cortical-subcortical connectivities in the genesis of psychosis are interesting subjects for further study. 40 references.
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New Heights in Speech Research Source: ADVANCE for Speech-Language Pathologists and Audiologists. 8(26): 6-9. June 29, 1998. Summary: This article, from a professional newsletter for audiologists and speech language pathologists, hypothesizes that the same brain regions that govern thought may be involved in controlling speech. The author reports on a research study in which motor control and cognitive functions were measured in high-altitude, oxygen-poor situations (mountain climbing). Time needed to comprehend simple spoken English sentences increased by 50 percent at higher altitudes. The researchers theorized that the deterioration in cognition and motor control observed at higher altitudes might be due to selective dysfunction of the basal ganglia, the same brain structures implicated in
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studies of patients with Parkinsons disease. However, some tasks are unaffected at high altitudes. For example, no negative effect was found on some cognitive tests, such as the confrontation naming test, digit span tests, and the odd-man-out test. The investigators also established the viability of remote monitoring of neural functions, a precursor to determining how to implement this tool in a practical way. The article concludes with the contact information for the clinicians and researchers interviewed. 5 figures. •
Frontal Lobe Volume in Patients With Huntington's Disease Source: Neurology. 50: 252-258. January 1998. Summary: This journal article describes a study of frontal lobe volume in 20 patients with Huntington's disease (HD). The participants included 10 patients who were mildly affected and 10 who were moderately affected from the Baltimore Huntington's Disease Project, Johns Hopkins University School of Medicine, Maryland, and 20 healthy, matched controls. Magnetic resonance imaging was used to measure gray and white matter volumes within the frontal lobes. Symptom severity was assessed with the Quantified Neurological Examination, and cognitive function with a neuropsychological test battery. In mildly affected patients, frontal lobe gray and white matter volumes were almost identical to those of controls, despite clearly abnormal basal ganglia. Moderately affected patients exhibited significant reductions in total frontal lobe volume (17 percent) and frontal white matter volume (28 percent). Reductions in frontal white matter volume, but not total frontal lobe volume, were disproportionately greater than overall brain volume reductions. Frontal lobe volume correlated with symptom severity and general cognitive function, but these correlations did not remain significant after controlling for total brain volume. The authors conclude that cognitive impairment and symptom severity are associated with frontal lobe atrophy but that this association is not specific to the frontal lobes. 1 figure, 3 tables, 28 references.
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Role of Copper in Wilson's Disease Source: Contemporary Gastroenterology. p. 45-47, 50-51. July-August 1991. Summary: Wilson's disease is an autosomal recessive disorder, characterized by progressive deposition of copper in the liver and the basal ganglia of the brain. This article reviews the role of copper in Wilson's disease. The author notes that once adequate copper chelation has been achieved, lifelong maintenance therapy with penicillamine, a low-copper diet, and oral zinc may suffice. The alternative therapy is liver transplantation. Transplantation has been proposed for the treatment of patients with irreversible neurologic manifestations of Wilson's disease, since slow but complete resolution of neurologic symptoms occurs after liver transplantation. However, this therapy is controversial when hepatic function is not impaired. One sidebar reviews the pathogenesis of copper overload. 3 figures. 3 tables. 13 references.
Federally Funded Research on Basal Ganglia The U.S. Government supports a variety of research studies relating to basal ganglia. 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
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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
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database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. 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 basal ganglia. 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 basal ganglia. The following is typical of the type of information found when searching the CRISP database for basal ganglia: •
Project Title: A MOUSE MUTANT AS A MODEL OF SCHIZOPHRENIA Principal Investigator & Institution: Horowitz, Judith M.; Psychology; Medaille College 18 Agassiz Cir Buffalo, Ny 14214 Timing: Fiscal Year 2002; Project Start 16-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The transgenic ckr mice expressing an insertional mutation develop a progressive behavioral phenotype with motor symptoms resembling those seen in schizophrenia. As schizophrenia is a progressive brain disease of early development that affects forebrain neurons and circuits and ultimately behavior, there may be a relationship between disrupted forebrain development and basal ganglia dysfunction produced by the above insertional mutation. Here we will test this possibility by characterizing the behavioral deficits in ckr mice using a battery of behavioral tests selected to measure aspects of locomotion, hyperactivity, circling and sensorimotor gating. Further, we will test the ability of atypical antipsychotic agents and glutamate receptor agonists at preventing or attenuating the motor dysfunctions in ckr mice. As it is likely that the basic cellular and molecular mechanisms for initial regional and circuit differentiation in the forebrain is similar in most mammals, we propose to examine aberrations in forebrain development in the ckr mouse. This hypothesis is supported by preliminary studies that show enlargement of the lateral ventricles and a paucity of myelin fibers in the transgenic mouse striatum. To accomplish these research aims, the use of various combinations of immuno- and in situ hybridization and histochemical experiments, magnetic resonance neuroimaging techniques, and discrete pharmacological and behavioral manipulations will be used to elucidate further the cause and course related to the pathophysiology of schizophrenia. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: A2A SENSITIZATION
ADENOSINE
RECEPTORS
IN
PSYCHOSTIMULANT
Principal Investigator & Institution: Schwarzschild, Michael A.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 25-JUL-2001; Project End 31-MAY-2006 Summary: The adenosine A2A receptor offers a novel and compelling target for the modulation of addictive behaviors. Its expression in brain is largely restricted to the nucleus accumbens and straitum, where dopamine, glutamate and other neurotransmitters contribute to the sensitizing and reinforcing effects of psychostimulants. The striatal A2A receptor can modulate the release of these (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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neurotransmitters as well as their postsynaptic effects. In addition, it influences both the acute behavioral effects of psychostimulants, and (based on our preliminary studies) the behavioral sensitization induced by repeated psychostimulant exposure. These discrete anatomical, neuromodulatory and behavioral features point to an underappreciated role of A2A receptors in basal ganglia physiology and addiction biology. We propose (in response to NIDA PA-99-033) to investigate the role of the A2A receptor in behavioral sensitization and self-administration models of psychostimulant addiction. Our core hypothesis that A2A receptor inactivation attenuates the behavioral and biochemical changes induced by repeated psychostimulant administration will be systematically tested using complementary genetic and classic pharmacological approaches to A2A receptor inactivation. Specific Aim 1 will characterize the attenuation of amphetamineinduced locomotor sensitization and cocaine self-administration observed in A2A receptor knockout (A2A KO) mice. The effects of A2A receptor antagonists on the development and expression of psychostimulant-induced sensitization will then be correlated with the A2A KO phenotype. Specific Aim 2a will explore A2A receptorfacilitated neurotransmitter release as potential presynaptic mechanism of behavioral sensitization. In vivo microdialysis studies will focus on how A2A receptor inactivation affects the enhanced release of dopamine, glutamate and acetylcholine that contributes to behavioral sensitization. Specific Aim 2b seeks to identify postsynaptic mechanisms involved in A2A receptor regulation of behavioral sensitization. We will examine the effects of A2A receptor deficiency on a potential mediator (deltaFosB) and modulator (NAC-1) of the postsynaptic adaptations sustaining behavioral sensitization. Together these studies will clarify the role of A2A receptors in psychostimulant-induced addictive behaviors, and thus may encourage the development of novel, specific strategies for treating psychostimulant abuse and related addiction disorders Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADVANCED METHODS FOR MICROELECTRODE GUIDED NEUROSURGERY Principal Investigator & Institution: Mewes, Klaus; Neurology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 14-SEP-2000; Project End 31-MAY-2004 Summary: (Verbatim from the Applicant's Abstract) Development and clinical testing of an improved brain mapping and lesioning system is proposed. An improved MRI scan protocol, the intraoperative use of patient-specific MRI data and automation of major components of the microelectrode-guided neurosurgical procedure are key features of this system. These efforts are anticipated to improve the accuracy of lesion and/or deep brain stimulating electrode placement and to increase the efficiency and safety of this procedure. Increased usage and availability of this class of procedures is expected due to 'ease of use' characteristics achieved by automating many of the difficult and time consuming tasks. System development and enhancement will be based on the microelectrode-guided pallidotomy procedure pioneered at Emory University. A high resolution, high contrast MRI protocol will be developed for better visualization basal ganglia (BG) structures and greater spatial accuracy. It will be used to generate 3D mapping templates from patient-specific data volumes. Software for intra-operative useage will have the following functions: 1) automatic classification of neuronal discharge patterns and detection of BG nuclear boundaries, 2) automated detection of sensory-motor driving and visual evoked responses, 3) generation and co-registration of microelectrode trajectory plots with MRI incorporating data from 1 and 2, and 4) automated best-fit analysis to correlate recording track information with the MRI-based
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patient-specific MRI data volume. The system performance for neuronal pattern classification and BG nuclear boundary detection, sensory-motor driving and visual evoked response detection, microelectrode track generation, and track to template bestfit analysis will be compared individually to that of human experts. Upon achieving successful performance, a working prototype will be developed near the end of the second year that integrates these components and the clinical evaluation phase of the system will begin. Lesion accuracy, operating time, and a number of tracks required using the proposed system will be compared to similar data from procedures performed at Emory University using previous methods and technology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AGE MODERATES HIV-RELATED CNS DYSFUNCTION Principal Investigator & Institution: Becker, James T.; Professor; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): During the course of the HIV/AIDS epidemic there has been one constant - ten percent of all new cases occur in adults over the age of 50. In spite of this, the vast majority of all HIV/AIDS research has focused or individuals younger than 50. With the increasing survival of AIDS patients, and the unrelenting rate of new infectiodcases, the number of AIDS patients over 50 years of age is growing. Our lack of understanding about how age and HIV/AIDS interact is becoming increasingly problematic, no more so than in the area of the neurocognitive manifestations of AIDS, since age is itself an important predictor of neurocognitive syndromes- In spite of the known links between age and various neuropsychiatric disorders - including dementia it has only been recently that much attention has been paid to the possible interactions between HIV/AIDS and aging and neuropsychiatric presentation. The purpose of this study is to compare and contrast neuropsychological deficits, including brain structural and functional abnormalities associated with HIV/AIDS as a function of chronological age. In particular, we will characterize the neuroimaging and neuropsychological defects in older individuals with AIDS focusing on two distinct neuropathologies that can lead to impairment - one via mesial temporal dysfunction (aging), and the other via basal ganglia dysfunction (AIDS). By carefully characterizing the neuropsychological deficits (including those identified using brain imaging technology) we will be better able to understand the interactive effects of agingand HIVIAIDS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
•
Project Title: AGING AND DOPAMINE GRAFTS IN PARKINSONIAN MONKEYS Principal Investigator & Institution: Collier, Timothy J.; Professor; Rush University Medical Center Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-MAR-2004 Summary: (Verbatim from the Applicant's Abstract) Transplantation of embryonic dopamine (DA) neurons as an experimental therapy for Parkinson's disease (PD) is currently under evaluation. The non-human primate treated with the neurotoxin MPTP has served as an important animal model for the disease and the grafting paradigm, and has had significant predictive value for results of early clinical trials. Despite some encouraging clinical findings, relative survival of grafted DA neurons is low and improvement of behavioral symptoms is incomplete. Part of the disparity between results in animals and PD patients may relate to failure of animal studies to model certain characteristics of potential recipients of graft therapy that impact significantly on
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the environment of grafted cells. One characteristic of this patient population that can be examined in animals is the influence of chronological age of the transplant recipient. The interactions between age-related changes inherent to this system in graft recipients, the response of the aging system to accelerated loss of nigral DA neurons, and the impact these changes have on the environment for grafted tissue only recently have received attention. We have found that the viability and function of grafted DA neurons is profoundly diminished in DA-depleted aged rats. In addition, these aged animals exhibit important deficits in compensatory responses to DA depletion including decreased striatal neurotrophic activity. Recent clinical results also suggest diminished graft efficacy in elderly patients. Advancing chronological age of the transplant recipient may represent a previously under-appreciated risk of diminished graft viability and function that may mandate study of novel grafting strategies 1 to achieve good therapeutic results. It is the goal of this proposal to evaluate the influence of chronological age of the host on graft viability and function in MM?-treated non-human primates. Tissue from single donors will be divided for implantation into pairs of young adult and aged hemiparkinsonian monkeys, with behavioral, mophological, and biochemical techniques employed to study rates of apoptosis in grafts, survivai, neurite outgrowth and release of DA from grafted cells, and receptor, metabolic and -trophic responses in the host. Additional analyses will examine aging-related changes in microvasculature and oxidative stress in the graft environment. These studies will provide valuable information on the response of the aged brain to accelerated DA neuron loss, the interaction between aging in the host and graft viability, indicate mechanisms of intervention with graft survival and function in the aged brain, and will aid in matching patients with the optimal therapeutic approach. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AGING OF CENTRAL DOPAMINERGIC SYSTEMS IN PRIMATES Principal Investigator & Institution: Gash, Don M.; Professor and Chair; Anatomy and Neurobiology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 18-FEB-1997; Project End 31-JAN-2008 Summary: (provided by applicant): Behavioral slowing is one of the cardinal features of human aging, contributing to the debilitating deterioration of motor functions in senescence. Our principal hypothesis for the past five years of research on this Program Project has been that changes in central dopaminergic pathways constitute a fundamental component of age-associated motoric declines. Converging evidence from our studies and others are providing strong support for this hypothesis. Our experimental plan for the next five years is designed to further our understanding of CNS processes underlying behavioral slowing and analyze therapeutic approaches for intervention. Specifically, our studies focus on the dopamine (DA) neurons in the substantia nigra (SN) and their projections to the caudate nucleus, putamen and globus pallidus of the basal ganglia. The proposed studies will analyze key junctions in the neural circuitry regulating motor functions in the basal ganglia, using behaviorally characterized female rhesus monkeys ranging in age from young adulthood to old age (5-25years+) as a model of human aging. Collectively, the three Projects and three supporting Cores in this Program will critically test the following hypotheses: Hypothesis 1 - That while changes in dopaminergic functions occur throughout the basal ganglia, alterations in neural processing in the SN is a principal component of age-associated motor declines. Hypothesis 2 - That functional changes in the basal ganglia dopaminergic system, including in tyrosine hydroxylase (TH), dopamine transporters (DAT) and DA receptors, are closely associated with age-associated motoric
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declines. Hypothesis 3 - That anatomical changes in normal aging in the basal ganglia are less predictive than functional changes of age-associated declines in motoric performance. Hypothesis 4 - That local administration of the potent dopaminergic trophic factor GDNF (glial cell line-derived neurotrophic factor) into the SN significantly repairs and restores age-associated declines in SN dopaminergic functions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASTROCYTE CYTOKINE EXPRESSION/ION TRANSPORT IN ADC Principal Investigator & Institution: Benos, Dale J.; Professor & Chair; Physiology and Biophysics; University of Alabama at Birmingham Uab Station Birmingham, Al 35294 Timing: Fiscal Year 2002; Project Start 01-SEP-1993; Project End 31-JUL-2004 Summary: Central nervous system (CNS) involvement often occurs in individuals infected with human immunodeficiency virus type-1 (HIV-1). The most common clinical syndrome characterized by cognitive, motor, and behavioral disturbances is the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) or HIVassociated dementia (HAD), and is unique to HIV-1 infection. Although anti-retroviral agents (RT and protease inhibitors) are being used in HIV-infected individuals, it is not yet clear how these agents will affect HAD or if these drugs can even penetrate the brain. Thus, a major problem facing HAD patients is the that drugs used to combat systemic viral infection may not influence the CNS, a potential reservoir for virus. Because the physiological status of the brain in AIDS patients cannot be readily sampled, there is a critical need for the development of non-invasive techniques to detect and monitor the extent of HIV- associated cognitive/motor disorders. In this application, we intend to translate basic science findings obtained in the previous grant period to the human, and perform clinical cognitive studies on HIV-infected patients. We will develop non- invasive methodologies, based on 31P nuclear magnetic resonance (NMR) spectroscopy, eventually to investigate how pharmacological and/or immunological manipulations can affect the pathological and psychomotor abnormalities in humans infected with HIV-1. We will also correlate such brain metabolic changes with the degree of dementia in HAD patients. This will be accomplished through he neuropsychological assessment of participants. Thus, a sophisticated array of experimental approaches will be used to define molecular mechanisms underlying the pathophysiology of HAD, which ultimately will be critical for the development and assessment of new therapeutic strategies. There is one specific aim: 1) to test the hypothesis that cerebrospinal fluid (CSF) viral load, CD4+ cells, and/or cytokine content correlates with increases in pH in various regions of the brain, specifically the basal ganglia and cerebellum. In addition, neuropsychological testing will be performed on all subjects enrolled in this study in an effort to a) assess subject neurocognitive/motor status and b) to link the clinical developmental stage of dementia with CSF viral load and brain pH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: AUGMENTATION NEUROSURGERY
OF
ACCURACY
FOR
IMAGE-GUIDED
Principal Investigator & Institution: Skrinjar, Oskar; Biomedical Engineering; Georgia Institute of Technology 505 10Th St Nw Atlanta, Ga 303320420 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2006 Summary: (provided by applicant): The ultimate goal of this work is to increase the success rate of the microelectrode-guided surgery and consequently improve the quality
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of life of patients suffering from movement disorders. To achieve this goal, methods are proposed to augment the navigational accuracy of the surgery without interfering with standard portions of the procedure. To successfully target a specific brain location (e.g. the best location for implantation of a permanent stimulating electrode), one needs to accurately know the boundaries of the neighboring structures of interest (in this case: Basal Ganglia, Thalamus, Sub-thalamus, optic tract). In the standard procedure, these boundaries are obtained from a brain atlas. However, the accuracy of the 3rocedure is adversely affected by: the shape and size difference in anatomy of the brain atlas and of the 3atient, and by intraoperative brain deformation. To address these problems the following aims are proposed: AIM 1. Available brain atlases will be explored and the highest-resolution one will be selected. A method for building 3D surface models of the structures of interest from the atlas images will be designed. The atlas will be represented by its images stacked into a 3D image volume and by a collection of 3D surface models. AIM 2. A highly accurate method for nonrigid alignment of the atlas 3D image and the patient's preoperative MR scan will be developed. This alignment will be applied to the atlas models to adjust their position, shape, and size. This will bring the models into registration with the patient MR scan making them patient specific. AIM 3. The locations of boundaries between structures of interest along the microelectrode tracks are recorded intraoperatively. This information will be used to fine-tune the patient specific models in order to make them more accurate. AIM 4. The intraoperative brain deformation will be analyzed, its affect on the accuracy of the microelectrodeguided surgery will be investigated, and methods for its compensation will be explored. AIM 5. The proposed methods will be clinically tested on 50 cases of microelectrodeguided surgery. Although the proposed methods will be applied to the microelectrodeguided surgery, they can be extended to other image-guided neurosurgical procedures, including tumor removal and epilepsy surgery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BASAL GANGLIA CIRCUITRY IMMEDIATE EARLY GENE EXPRESSION Principal Investigator & Institution: Wirtshafter, Robert D.; Psychology; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-DEC-1998; Project End 31-DEC-2003 Summary: (from Abstract) The long term objective of the current proposal is the attainment of a greater understanding of the functional organization of the basal ganglia. Substantial evidence suggests that many neurological and psychiatric disorders, including Parkinson's disease, Huntington's disease, Sydenham's chorea, torsion dystonia, Tourette's syndrome and schizophrenia, may result from abnormalities in the activity of these nuclei. Progress in understanding the etiology of these disorders, and in developing treatments for them, is largely dependent on advances in understanding the basic nature of basal ganglia functioning. The proposed experiments are designed to examine basal ganglia by using the immunocytochemical detection of immediate early genes (IEGs) as markers for neurons affected by various behavioral or pharmacological manipulations. The striatum is the largest nucleus within the basal ganglia and is the primary terminus of input into this system. The first set of studies will examine the pharmacological and behavioral control of IEG expression within this structure with emphasis on the patterning of IEG expression with respect to the striosome/matrix compartmentation of the striatum. The striatum contains a number of neuroactive compounds including dopamine, serotonin, adenosine, acetylcholine and substance P and the role played by these substances in controlling striatal IEG
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expression will be examined. The applicants will also examine the role of dopamine in IEG expression induced by shuttling behavior and characterize the cells that express IEGs under these conditions. Events occurring within the striatum can only influence behavior by affecting the activity of neurons within other parts of the brain. The second group of studies will therefore use IEG expression as a tool to investigate the basic organization of extrastriatal circuitry related to the basal ganglia. Experiments will examine the ability drugs microinjected directly into the striatum, or other basal ganglia nuclei, to influence IEG expression at extrastriatal sites. Other studies will examine the effects of lesions within the basal ganglia on the IEG expression induced by systemic administration of dopaminergic drugs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BASAL GANGLIA DISCHARGE PATTERNS IN PARKINSONISM Principal Investigator & Institution: Wichmann, Thomas N.; Associate Professor; Neurology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 15-JUN-2001; Project End 31-MAY-2006 Summary: (Verbatim from the Applicant's Abstract) The basal ganglia are part of larger circuit that involves thalamus and cortex. Cortical inputs reach striatum and subthalamic nucleus (STN), and are transmitted via internal pallidal segment (GPi) and substantia nigra pars reticulata (SNr) to influence the activity of thalamocortical neurons. The function of this circuitry is disturbed in Parkinson's disease because of loss of dopamine in the basal ganglia. Besides changes in discharge rates, basal ganglia neurons also develop significant abnormalities in their discharge patterns in parkinsonism. One of the most salient abnormalities is the appearance of synchronized oscillatory discharge in STN, the external pallidum (GPe), GPi/SNr, and frontal cortex (detected by EEG). Available data suggest that this may result from altered activity along the cortex-STN-GPi/SNrthalamocortical route. With a combination of extracellular basal ganglia recordings and EEG, the proposed primate experiments explore the relationship between oscillatory activity in cortex and basal ganglia and will test the hypothesis that oscillatory discharge in the cortex-basal ganglia circuitry contributes to parkinsonism. The correlation studies under specific aim (S.A.) 1 assess the link between neuronal discharge in the basal ganglia (GPe, STN GPi, SNr) and EEG with simultaneous recordings in both brain regions. The importance of striatal or extrastriatal dopamine loss for the development of oscillatory discharge in parkinsonism will be tested under S.A. 2 by studying changes in oscillatory activity in basal ganglia and cortex induced by microinjections of the dopamine receptor agonist apomorphine at striatal and extrastriatal basal ganglia sites in parkinsonian animals. The experiments under S.A. 3 will test whether blockade of glutamate receptors in STN (blocking corticosubthalamic inputs) reduces oscillatory activity in basal ganglia and cortex. Finally (S.A. 4), the hypothesis will be tested that synchronized oscillatory discharge in the basal ganglia, induced by electrical stimulation of STN with bursts of stimulation pulses at burst rates between 2 and 30 Hz, disrupts motor performance and induces parkinsonian motor abnormalities in normal monkeys. These studies will help to understand the significance of oscillatory discharge in the basal ganglia and cortex in parkinsonism. This may provide guidance in the development of drug treatments directed at normalizing abnormal discharge patterns, and may help to understand the mechanism of action of existing treatments for Parkinson's disease, including dopamine receptor agonists, glutamate receptor antagonists, and deep brain stimulators. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BASAL GANGLIA EXPRESSION OF TORSINA IN TRANSGENIC MICE Principal Investigator & Institution: Ehrlich, Michelle E.; Professor of Neurology; Neurology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): Early-onset dystonia (DYT1) is caused by an autosomal dominant mutation in the torsinA protein. Dystonia is manifested by sustained muscle contractions, appearing as movements or abnormal postures, which may be focal or diffuse. TorsinA expression is diffuse within both the central nervous system and peripheral organs. Therefore, similar to many other neurologic diseases, it is important to determine how a diffusely expressed protein can cause localized disease. In the case ofdystonia, extensive evidence points to a key, although not necessarily unique, dysfunction within the basal ganglia. With recent progress in this laboratory in the identification ofa striatal specific promoter active in transgenic mice, along with the expertise of collaborators, this group of investigators is in a unique position to test hypotheses regarding the role of the basal ganglia in dystonia. Simultaneously, testing of these hypotheses may lead to valuable animal models of the disease. This is an R21 proposal to create these transgenic models. Specific Aim 1 is to create transgenic mice expressing mutated human torsin A in the l) substantia nigra, under the direction of the human tyrosine hydroxylase promoter and 2) in the striatum, under the direction of the mouse DARPP-32 promoter. SPECIFIC AIM 2 is to initiate the analysis of these mice, and to determine whether selective expression of torsinA in the substantia nigra and/or striatum results in 1) a movement disorder in transgenic mice, as determined by rotarod testing and/or 2) abnormalities ofdopaminergic neurotransmission in the striatum, as determined by induction of c-los expression following administration ofa psycho stimulant, i.e. a dopamine agonist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BASAL GANGLIA FUNCTION IN OBSESSIVE COMPULSIVE DISORDER Principal Investigator & Institution: Rauch, Scott L.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: The goals of this project are to test specific hypotheses about the pathophysiology of obsessive compulsive disorder (OCD) using functional MRI (fMRI) and cognitive neuroscience methods. The basal ganglia have been implicated in the pathophysiology of OCD and also in the normal mediating anatomy of implicit (i.e., nonconscious) learning. We have developed an fMRI paradigm to measure activity within components of the basal ganglia during the performance of an implicit learning task. In preliminary functional imaging studies, we have observed an abnormal activation profile in medication-free subjects with current OCD. Specifically, in comparison to normal control subjects, patients with OCD exhibit a failure to activate right striatum, and an absence of thalamic deactivation, as well as aberrent medial temporal activation (i.e., not found in normal subjects). These results are consistent with evolving neurobiological models of OCD and basal ganglia function. The current proposal aims to: 1) use this fMRI paradigm to replicate and elaborate upon the above findings in a larger cohort of medication-free patients with active OCD and matched normal comparison subjects; 2) determine the specificity of the findings in OCD by
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studying psychiatric comparison subjects; and 3) further investigate the neuropsychological consequences of the abnormal activation profile observed in OCD. It is anticipated that this approach will yield new information regarding the pathophysiology of OCD and related disorders, while providing new insights about the normal function of the basal ganglia and the mediating anatomy of normal learning. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BASAL GANGLIA FUNCTION--BASIC MECHANISMS AND EFFECTS Principal Investigator & Institution: Assad, John A.; Assistant Professor; Neurobiology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: The basal ganglia (BG) are a set of subcortical nuclei that play a crucial role in the control of voluntary movements. Their importance is underscored by diseases of the BG, such as Parkinson's disease, which compromise the initiation and execution of voluntary movements. While much is known about the general organization of the BG, fundamental questions remain about their role in the normal control of movement. These questions are particularly relevant given the renewed interest in restorative neurosurgical procedures, such as chronic electrical stimulation. that target the BG to relieve Parkinsonian symptoms. The main goal of this is to understand the role of the BG in the normal control of movement, using the awake behaving macaque monkey as an experimental system. The first aim addresses an intriguing paradox about the BG: while diseases affecting the BG cause problems with initiating voluntary movements, most neurophysiological studies have found that neuronal activity in the BG occurs too late to play a role in movement initiation. However, in most of these studies the movements were in response to an external sensory stimulus. There is evidence from Parkinsonian patients that stimulus-cued movements are less severely affected than selfinitiated movements. We will thus examine whether the BG play a special role in selfinitiated movements - self-initiated with respect to either when a movement is made or which movement is made. The second aim addresses the roles of the direct and indirect BG pathways. The output of the BG is influenced by two distinct pathways with opposing effects on movement: a direct pathway from the striatum which facilitates movement, and an indirect pathway via the subthalamic nucleus (STN) which inhibits movement. While the identification of these pathways has provided a useful framework for understanding movement disorders, many questions remain about their roles in normal movement. We will test one hypothesis, that the two pathways may act in concert to "select" a specific movement among competing possibilities of movement, by examining how neurons in the output nuclei of the BG are affected by electrical inactivation of the STN. For this purpose, it will be necessary to examine the neuronal effects of electrical stimulation in the STN. Little is known about the neuronal effects, even though STN stimulation is now being used to treat Parkinsonian symptoms in human patients. We will directly measure the neuronal effects of electrical stimulation in the STN, and examine how these effects vary with the parameters of stimulation. For this we will develop and test new multielectrode techniques for recording from and electrically stimulating multiple deep brain sites simultaneously. The combined basic studies and technical innovations will increase our understanding of the role of the BG in normal movement and movement disorders, and will hopefully provide new approaches for treating Parkinsonian conditions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BASAL GANGLIA NEUROPHYSIOLOGY DURING DBS IN RATS Principal Investigator & Institution: Chang, Jing-Yu; Assistant Professor; Physiology and Pharmacology; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): Parkinson's disease (PD) is a degenerative neurological disorder affecting millions of patients all around the world. Renewed use of the deep brain stimulation (DBS) method provides a new opportunity for treating PD. A key issue to improve the treatment is to fully understand the neural mechanisms underlying the therapeutic effects of DBS. In this proposed study, two unique techniques developed in our laboratory: the chronic multiple-channel single unit recording and rat model of DBS, will be employed to study the neural responses in multiple basal ganglia regions during behaviorally effective DBS in rat model of Parkinsonism. A first objective is to establish a rodent model of DBS in Parkinsonian conditions. The effects of DBS will be evaluated in dopamine lesioned rats performing treadmill locomotion and limb use asymmetry tests. Locomotor d deficits during treadmill walking and imbalance usage of forelimb in vertical exploratory behaviors will develop after unilateral dopamine lesion. High frequency stimulation (HFS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) will then be applied to alleviate these motor abnormalities. The degree of dopamine depletion in the basal ganglia will be detected by immunohistochemical staining of dopamine marker and this result will be correlated with the severity of motor deficits and DBS effects. Second, the basal ganglia neural responses following a dopamine lesion and during behaviorally effective HFS will be examined. Single neural activity and local field potential in the striatum globus pallidus, STN and SNr will be recorded simultaneously in a 64 channel recording system in the rat performing these behavioral tests. Neural responses following dopamine lesion will help us to understand the pathophysiologic process of developing Parkinsonian syndromes while the neural responses during behaviorally effective HFS will shed light on how DBS can restore normal information processing in the basal ganglia neural circuits that are disrupted following dopamine lesion. Several important improvements on recording and stimulation techniques will be made in cooperation with Biographic Inc. to achieve optimal conditions for high frequency stimulation and artifact free recording. The goal of this study is to explore the basic neural mechanism underlying the therapeutic effects of DBS and the knowledge obtained form this study will help us to improve the clinical treatment of PD with DBS method. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BLOOD FLOW CHANGES AND ANTIPSYCHOTIC DRUG ACTION Principal Investigator & Institution: Lahti, a C.; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-MAY-1999; Project End 31-JAN-2003 Summary: (adapted from applicant's abstract): Antipsychotic drugs reduce psychosis, induce motor effects, and have miscellaneous other actions. The brain substrates of these effects, beyond actions on receptor populations are poorly understood. The investigator proposes to determine the dynamic time course of the effects of antipsychotics on regional cerebral blood flow (rCBF) using PET and 15OH2 in drug-free schizophrenia patients as a direct pharmacodynamic assessment of drug action in the human brain. rCBF measurements would span the pharmacokinetic time course. The investigator proposes to characterize the dynamic time course of rCBF alterations following the acute
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and six days of administration of two different antipsychotic drugs, the traditional antipsychotic haloperidol and the newer antipsychotic olanzapine. The ability of the changes in rCBF following acute and subacute antipsychotic administration to predict subsequent treatment response would also be evaluated. Based on their preliminary findings, the investigators hypothesize that acute and subacute drug-induced rCBF changes in selected regions will predict treatment response for positive symptoms (anterior cingulate and medial frontal cortex), for negative symptoms (middle frontal cortex and inferior parietal cortex), and motor side effects (basal ganglia). The proposed subacute drug administration regimen would approximate a pharmacokinetic steady state for both antipsychotics. An additional aim of the proposal is to compare the rCBF changes induced by haloperidol versus olanzapine during the scanning sessions obtained with acute and subacute (steady state) antipsychotic administration. The investigator proposes that the pattern of activation in the basal ganglia will best discriminate the two antipsychotic agents. These studies will hopefully provide rCBF correlates of antipsychotic activity. This information will allow the development of hypotheses related to drug mechanism of action, as well as potential surrogate markers of drug action. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOTHERAPY FOR HUNTINGTON'S DISEASE Principal Investigator & Institution: Hersch, Steven M.; Associate Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: Transcriptional modulation is a promising approach to neuroprotection in Huntington's disease (HD). Our preliminary data indicates that transcriptionally active compounds like histone deacetylase (HDAC) inhibitors and aureolic acid antibiotics including mithramycin are among the most promising potential treatments available for HD. Phenylbutyrate is the HDAC inhibitor most developed for human use and with the best evidence for brain bioavailability. Mithramycin is used to treat Paget's disease, several types of malignancy, and hypercalcemia of malignancy and has the greatest efficacy in HD transgenic mice to date. The safety, tolerability, and efficacy of these agents is completely unknown in HD or other neuro-degenerative disorders. This project will test the feasibility of these medications in HD in large scale trials of efficacy. In aim one, we will examine whether phenylbutyrate is safe and tolerable for use in HD patients and whether it can improve any symptoms or biological markers of HD. A randomized double-blind placebo-controlled long-term safety and tolerability trial of phenylbutyrate in HD patients will be performed. We will assess the impact of phenylbutyrate treatment on: standardized clinical ratings of motor function, cognition, behavior, and functional capacity. We will also examine In vivo markers of neurodegeneration and transcriptional modulation including proton magnetic resonance spectroscopy for lactate and NAA, and peripheral markers of transcriptional modulation, histone acetylation, and phenylbutyrate activity. In aim two, we will examine whether mithramycin is safe and tolerable in long-term use in HD patients and whether it can improve any symptoms or biological markers of HD. Following an open label dose-ranging trial in which a maximally tolerated dose will be determined, subjects will be randomized into a double-blind placebo controlled safety and tolerability trial of mithramycin using intermittent infusion. We will also assess the impact of mithramycin treatment on; standardized clinical ratings of motor function, cognition, behavior, and functional capacity. We will examine In vivo markers of
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neurodegeneration including proton magnetic resonance spectroscopy of the basal ganglia and cortex, and peripheral markers of mithramycin activity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHRONIC ALTERATIONS IN RESPONSE TO GLUTAMATE,GABA, DOPAMINE
ELECTROPHYSIOLOGICAL
Principal Investigator & Institution: Levine, Michael S.; Professor; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2003 Summary: The hypothesis to be examined in this project is that loss of nigrostriatal dopamine (DA) neurons in Parkinson's disease (PD) and in animal models of PD1 as well as the pharmacological and surgical treatments of PD alter the functional characteristics of glutamate, Y-amino butyric acid (GABA) and DA receptors in subthalamic nucleus (STN) neurons. The STN has become important for understanding changes in basal ganglia function in PD since it is clear that one outcome in PD is a marked change in the activity of STN neurons. The current model of why STN neuronal activity changes is based on the hypothesis that DA loss in PD leads to a release of the STN from tonic inhibition by the extemal pallidurn. Increased activity of the STN, the only excitatory projection nucleus in this systern1 then provides the major excitatory drive onto basal ganglia outputs. There is a growing consensus that this model of PD is unsatisfactory. Thus, this project is aimed at examining other alternatives. We will use in vifm electrophysiology in STN slices to examine changes in receptor function after unilateral DA depletion and after three treatment paradigms, the classic, chronic LDOPA treatment, the recent approach of deep brain stimulation of the STN, and a novel approach of implanting GABA-producing cells into the STN. There are four aims that will test our central hypothesis. Aim I will determine if DA depletion alters responses mediated by activation of specific glutamate receptor subtypes and GABA receptors in STN neurons. Aim II will determine if DA depletion alters subsequent DA modulation of responses mediated by activation of specific glutamate receptor subtypes and GABA receptors in STN neurons. Aim III will test the hypothesis that treatment with L-DOPA after DA depletion restores normal responses to the activation of glutamate, GABA/A and DA receptors in the STN. Aim IV will test the hypothesis that implantation of cells that produce excess GABA in STN or deep brain stimulation of STN after DA depletion (two procedures that silence STN neurons) alter abnormal responses induced by activation of glutamate, GABA/A, and DA receptors in either the entopeduncular nucleus (homologue of the internal pallidal segment of primates) and/or the substantia nigra pars reticulata. The results from this project, combined with those from Projects 1 and 3, will provide a more complete understanding of the mechanisms underlying changes in STN neural activity to design new, rational pharmacotherapies for PD that can use the STh as a therapeutic target. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COGNITIVE SEQUELAE OF METHAMPHETAMINE ABUSE Principal Investigator & Institution: Salo, Ruth E.; Psychiatry & Behavioral Sciences; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 956165200 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-MAY-2006 Summary: (provided by applicant): This application is to support a period of advanced training in multidisciplinary approaches to the study of substance abuse with a focus on
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methamphetamine [MA]. The candidate will acquire new knowledge in the fields of addiction psychiatry, pharmacology, neuroanatomy and neuropsychological assessment, providing the foundation to develop an independent research program that will examine the cognitive and neural sequelae of stimulant abuse. Additional training is needed to achieve this goal, as the study of substance abuse is new to the candidate and requires specialized knowledge related to the substances themselves as well as the behavioral results of long-term abuse. The candidate will work with a small group of talented mentors who will provide a solid background in addiction medicine, neurological research and cognitive assessment of substance abusers. The candidate will attend advanced courses in pharmacology, neuroanatomy, and participate in clinical rotations at substance abuse clinics (yrs 1-3) and neurobehavioral clinics (4-5). UC Davis is uniquely suited for the training and research goals of the candidate. The UC Davis School of Medicine offers advanced courses in pharmacology, neuroanatomy and clinical rotations, and staffs an ongoing program of neurobehavioral rounds and MRI/CT scan reading. The candidate's immediate goal is to assess cognitive performance in a group of MA dependent subjects, substance abusing controls, and focal lesion patients compared to healthy controls and to correlate the cognitive data with clinical symptomatology associated with substance abuse. The candidate will employ a focused battery of cognitive tasks that have been validated as measures of frontostriatal functioning and are believed to recruit the anterior cingulate [ACC], prefrontal cortex [PFC] and the basal ganglia, brain regions noted to be damaged following long-term MA abuse. This project will complement ongoing imaging studies of neural damage in stimulant abusers at UC Davis. The specific aims of the research proposed in this project are to measure: 1) the ability to suppress response conflict; 2) cognitive flexibility; 3) explicit and implicit memory processes; and 4) to correlate the cognitive findings with clinical symptomatology associated with stimulant abuse. The candidate's long-term career goal is to use the experience gained during this award to develop an independent research program that applies the approaches of cognitive neuroscience and clinical neuropsychiatry to the study of substance abuse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTINUITY OF LIMBIC CIRCUIT THROUGH THE BASAL GANGLIA Principal Investigator & Institution: Haber, Suzanne N.; Anatomy and Neurobiology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 30-SEP-1989; Project End 31-MAR-2008 Summary: (provided by applicant): Mental disorders, including schizophrenia, obsessive compulsive disorder (OCD) and drug addiction are linked to pathology in the prefrontal cortico-ventral striatal-thalamic circuit by imaging studies, post mortem anatomical studies, and basic research. Not only do these illnesses have a common circuitry, but they all emerge relatively early in life, primarily during adolescence or young adulthood. Anatomical, physiological and pharmacological studies in this circuit have been central in gaining insight into the mechanisms underlying mental health disorders. The structures involved include the prefrontal cortex, the ventral striatum (VS), the ventral pallidum/substantia nigra, pars reticulata (VP/SNr), and the medial dorsal N. of the thalamus (MD), which links the circuit back to cortex. During the previous funding period we: 1. defined the territory of the VS in primates, 2. identified important and unique cellular features of the VS, including BCL-2 positive cells and newly formed cells from the subventricular zone, and 3. identified the afferent connections to the midbrain dopamine. We also demonstrated a mechanism by which
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the limbic component of the basal ganglia impacts on other basal ganglia circuits through striato-nigro-striatal pathways. Finally, place of the thalamus in cortical regulation emphasizes newer concepts in control of cortico-cortical activity through its complex connections. We showed that an integrative network exists for the dorsal basal ganglia through its thalamic projections to different cortical layers and through a nonreciprocal cortico-thalamic projection. The general hypothesis of this proposal is that the combination of the impact of the ventral BG thalamocortico-thalamic network several cortical areas along with the unique cellular features of the ventral striaturn place this circuit in a position to be particularly vulnerable during adolescence. The experiments proposed here will test this hypothesis by: 1. delineating the thalamo-cortical network to determine how pathways through the ventral BG circuit can both reinforce its own loop and also impact on other cortical areas and BG circuits; 2. characterize bcl-2-positive neurons and newly formed cells and determine whether the unique cellular characteristics of the VS differ during adolescence, and whether they are particularly vulnerable to stimulation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTRIBUTION OF NEURAL MEMORY CIRCUITS TO LANGUAGE Principal Investigator & Institution: Ullman, Michael T.; Associate Professor; None; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2002; Project Start 30-SEP-1999; Project End 31-MAY-2005 Summary: The long-term objective of this project is to understand the brain bases of the mental lexicon, which contains memorized words, and the mental grammar, which contains rules that combine lexical forms into larger words, phrases, and sentences. We propose that the memorization and use of words is subserved by temporal-lobe circuits previously implicated in the learning and use of fact knowledge, whereas the acquisition and use of grammatical rules is subserved by frontal/basal-ganglia circuits previously implicated in the learning and expression of motor, perceptual, and cognitive "skills," such as riding a bicycle. Thus we posit that lexicon and grammar are linked to distinct brain systems, each of which is domain-general in that it subserves nonlanguage as well as language domains. This novel view contrasts with the two main competing theoretical frameworks. Although we share the perspective of traditional dual-system theories in positing that lexicon and grammar are subserved by distinct systems, we diverge from these theories where they assume components dedicated (domain-specific) to each of the two capacities. Conversely, while we share with singlesystem theories the view that the two capacities are subserved by domain-general circuitry, we diverge from them where they link both capacities to a single system with broad anatomic distribution. To distinguish our theory from the other two, we will probe the brain bases of irregular and regular word transformations, in which lexicon and grammar can be contrasted, while other factors are held constant. Irregular forms (e.g., dig-dug) are retrieved from memory, whereas regular forms (e.g., look-looked) require a suffixation rule. We predict, and have found in our preliminary studies, links among irregulars (lexicon), facts, and temporal- lobe circuits, and among regulars (grammar), skills, and frontal/basal-ganglia circuits. Single-system models do not make this set of predictions, and traditional dual-system theories do not predict the links with fact and skill use. Patients with either temporal-lobe or frontal/basal-ganglia damage will be given tasks probing the production and judgment of irregular and regular past tense inflection, plural inflection (mice, bees), and derivational morphology (solemnity, awkwardness), as well as measures of fact and skill use. Our specific aims are to test three hypotheses by probing for double dissociations between irregulars and regulars,
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and between facts and skills: (1) Lexicon is linked to temporal-lobe circuits, and grammar to frontal/basal-ganglia circuits. (2) These circuits also subserve fact and skill use, respectively. (3) The basal ganglia play a similar role in motor activity and grammatical rule use. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CONTROL OF SPIKING IN BASAL GANGLIA OUTPUT NEURONS Principal Investigator & Institution: Jaeger, Dieter; Assistant Professor; Biology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 10-APR-2000; Project End 31-MAR-2005 Summary: (Adapted from the Investigator's Abstract): The objective of the proposed research is to determine how the activity of neurons in the substantia nigra pars reticulata (SNr), one of the major output nuclei of the basal ganglia, is controlled by synaptic input. Simple network models of basal ganglia function and disorders assume that the activity of output neurons is determined by summing the amount of inhibitory and excitatory inputs received. It is clear, however, that single neurons have active intrinsic mechanisms by which synaptic inputs may be integrated in a highly complex non-linear fashion. These complex properties of synaptic integration will be examined in SNr neurons by combining in vitro whole cell recording, extracellular recording and computational modeling. First the passive and then the active properties of these neurons will be catalogued using whole-cell recordings in rat brain slices. These experiments will use current and voltage-clamping in conjunction with pharmacological blockade of various voltage- and ligand gated channels to isolate and characterize purely passive membrane properties and specific voltage-dependent conductances. Recorded neurons will be intracellularly stained and reconstructed histologically with Neurolucida, and the quantitative morphometric data obtained will be used along with the electrophysiological data to construct a compartmental model of SNr neurons. The model will be adjusted and fine tuned by comparing the behavior of the model to that of SNr neurons in whole cell recordings in vitro and in extracellular single unit recordings in vivo, while constraining the parameters to those obtained in the recording experiments. To study the mechanisms by which synaptic input controls activity, the parameters of synaptic inputs including the time courses and amplitudes of excitatory and inhibitory inputs will be measured and used in the model. Finally, realistic sequences of synaptic input, inferred from in vivo and in vitro recordings of SNr neurons will be input to the model to determine the input-output function of SNr neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DECREASED MOTOR THRESHOLDS IN DYSTONIA Principal Investigator & Institution: Blood, Anne J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2004; Project Start 05-APR-2004; Project End 31-MAR-2006 Summary: (provided by applicant): This is an application for an NINDS Exploratory / Developmental Grant (R21), entitled "Decreased Motor Thresholds in Dystonia." The goal of this project is to begin comparing the relative contributions of the motor and somatosensory systems to dystonic pathology by measuring brain activity in focal hand dystonic patients during motor and somatosensory tasks, working toward a hypothesis that the motor system plays a more primary role than the somatosensory system in dystonia. Specifically, we will make precise anatomical distinctions between motor and
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somatosensory cortical regions in our analysis of brain activity measured in dystonic patients during simple finger-tapping and finger-stimulation tasks (Aim 1). We will also use perfusion MRI and hemodynamic response timecourses to address some basic questions about "resting" activity in focal hand dystonic patients, both to guide our experimental design, and to potentially demonstrate how motor task repetition may lead to increased resting activity in dystonia (Aim 2). Finally, we will begin to develop tasks that engage the motor and somatosensory systems near activity threshold, with an overall aim of finding new ways of detecting patient/control differences in motor and somatosensory activity, and with a specific hypothesis that motor activity thresholds may be decreased in focal hand dystonia (Aim 3). In the future, we will use these tools to assess how botulinum toxin and other treatments of the disorder influence brain motor and somatosensory abnormalities, both in the short- and long-term. The proposed studies are expected to generate novel insights into neural mechanisms of dystonia, and eventually lead to significant improvements in the treatment of this debilitating disorder. The motor/somatosensory comparisons and "resting" activity measurements will allow us to gain new information about the relative roles of motor and sensory systems in dystonia, and increase the precision and accuracy of information gained from this and future brain imaging studies of this disorder. The "motor threshold" tasks are expected to provide evidence for decreased motor thresholds in dystonia that extend beyond primary motor cortex. Understanding the relative roles of motor and somatosensory systems in dystonic pathology will be a crucial step in determining which of the existing treatments for the disorder are most successful, and will allow us to better target new treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEEP BRAIN STIMULATION IN PARKINSON'S MODELS Principal Investigator & Institution: Anderson, Marjorie E.; Professor; Rehabilitation Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-MAY-2007 Summary: (provided by applicant): Although high-frequency deep brain stimulation (HF-DBS) in the globus pallidus or subthalamic nucleus has become a common technique used to treat drug-resistant symptoms of Parkinson's disease, the mechanisms by which HF-DBS exerts its effects are unknown. In the proposed studies, the ability of chronic administration of the insecticide rotenone, to produce an animal model of Parkinson's disease will first be tested in monkeys. Using PET imaging now available in the University of Washington Regional Primate Research Center, changes in dopamine innervation after administration of rotenone will be measured using a marker of the monoamine vescicular transporter that is present in dopaminergic nerve terminals. These changes will then be correlated, over time, with changes in behavior and with electrophysiological changes in the rate and pattern of discharge of neurons in basal ganglia-receiving areas of the thalamus. This model will then be used to couple the electrophysiological effects of HF-DBS, which can be recorded from basal gangliareceiving neurons of the thalamus, to the stimulation-induced changes in regional metabolism in the cortex and thalamus. PET imaging with the metabolic marker, [8-F] flurodeoxyglucose (FDG), will be used to measure metabolism. This technique has generally shown a relative hypermetabolism in the globus pallidus and thalamus of humans with Parkinson's disease and a relative hypometabolism in areas of the frontal cortex. Changes reported to be induced by HF-DBS have been mixed however. The combination of electrophysiology and metabolic imaging will allow us to address some of the discrepancies from the human literature. Special attention will be paid to the
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development of abnormal patterns of bursting behavior in the thalamus of monkeys treated with rotenone, as well as the effect of HF-DBS on burst behavior. This will test the hypothesis that some of the symptomatology of Parkinson's disease, and its relief using HF-DBS, is a consequence of abnormal patterns of activity in basal gangliathalamic-cortical circuits. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOPAMINE D2 AND ADENOSINE A2A ROLES:TREMULOUS MOVEMENTS Principal Investigator & Institution: Salamone, John D.; Professor; Psychology; University of Connecticut Storrs Unit 1133 Storrs-Mansfield, Ct 06269 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Symptoms of parkinsonism, such as akinesia, bradykinesia, and tremor, can be caused by degeneration of dopamine (DA) neurons, or by administration of DA antagonist drugs. Parkinsonism is characterized by a cascade of neurochemical events that reflect interactions between several neurotransmitters in the circuitry of the basal ganglia, including DA, acetylcholine, serotonin, GABA and adenosine. Within the last few years, increasing evidence has accumulated indicating that central adenosine neurons play an important role in modulating the functional circuitry of the basal ganglia. Several subtypes of adenosine receptors are involved in motor function, and anatomical studies have demonstrated that the adensonine A2A receptor subtype has a relatively high degree of expression within the striatum. Although several types of striatal cells contain some adensonine A2A receptors, these receptors are present in very high densities on striatopallidal neurons, which also tend to co-express DA D2 receptors and enkephalin. It has been suggested that antagonists of adenosine A2A receptors could have some potential utility as antiparkinsonian drugs. In a recent study from our laboratory, it was demonstrated that IP injections of the adenosine A2A antagonist, KF17837, also suppressed haloperidol-induced tremulous jaw movements, and reversed the locomotor suppression induced by this D2 antagonist. This profile of activity is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in antiparkinsonian effects in animal models. The proposed experiments are designed to investigate the role of the striatopallidal GABAergic pathway as a possible mediator of the putative antiparkinsonian effects of adenosine A2A antagonists. These proposed studies will focus on the tremulous jaw movement model, which is related to parkinsonian tremor. It is hypothesized that adenosine A2A antagonists are acting on striatopallidal GABAergic neurons that also express DA D2 receptors. In view of research showing that haloperidol increases extracellular GABA in globus pallidus, and that haloperidol-induced tremulous jaw movements are reduced by pallidal injections of bicuculline, it is hypothesized that doses of adenosine A2A antagonists that reduce jaw movement activity also will reduce haloperidol-induced increases in GABA release in globus pallidus. In addition, it is hypothesized that adenosine agonists and antagonists will interact to regulate the behavioral and neurochemical effects of haloperidol. These hypotheses will be investigated using studies that involve both systemic and intrastriatal injections of drugs that act upon A2A receptors, and the proposed work will involve a combination of behavioral pharmacology and microdialysis methods. This research is designed to enhance our understanding of the neurotransmitter interactions that are involved in the generation of tremulous movements, and to foster the development of new drugs for the treatment of parkinsonism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DOPAMINE MODULATION OF LIMBIC CORTICOACCUMBENS SYSTEM Principal Investigator & Institution: Onn, Shao-Pii; Neurobiology and Anatomy; Drexel University College of Medicine 245 N 15Th St Philadelphia, Pa 19102 Timing: Fiscal Year 2002; Project Start 09-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the Investigator's Abstract) Psychostimulant abuse in humans is known to produce states similar to both positive and negative symptoms of schizophrenia. Studies in rats have suggested that hyper-dopaminergic activity in subcortical structures such as nucleus accumbens leads to behavioral abnormality that may have relevance to positive symptoms. Emotional and cognitive deficits that characterize negative symptoms have been recently demonstrated in monkeys similarly treated with low doses of amphetamine and that in many ways resemble those identified in human amphetamine abusers. These cognitive deficits are believed to result from a dysfunction in the prefrontal cortex, thus linking to a clinical state of hypofrontality. A basic dysfunction of prefrontal-accumbens circuits is thought to be critical to the cognitive dysfunction, negative affect and abnormal reward-related behavior that is characteristic of schizophrenia and drug abuse. My working hypotheses is that in amphetamine treated rats there exists deficits in the excitatory drive from the limbic afferents from the entorhinal cortex and the mediodorsal thalamus to the prefrontal cortex and/or deficits in the dopamine modulation of these excitatory afferents. Thus the proposed experiments using in vivo intracellular recording and labeling techniques will compare and contrast information arising intracortically (eg entorhinal cortex; aim 1) and subcortically (eg mediodorsal thalamus; aim 2), the latter of which transmits basal ganglia outflow back to the prefrontal cortex. Lastly cortical processing in influencing basal ganglia outflow from the nucleus accumbens. I predict attenuated intracortical processing (aim 1) to occur in conjunction with an augmented basal ganglia feedback circuit, as marked by increases in both mediodorsal thalamusevoked activity in prefrontal cortex neurons (aim 2) and prefrontal cortex-evoked activity in nucleus accumbens neurons (aim 3), in amphetamine treated rats. The proposed study is of particular interest with respect to the deficit syndrome in schizophrenia and possibly other mental disorders such as drug addiction associated with negative affect and depression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DOPAMINE REGULATION IN PARKINSONIAN RAT BY GENE THERAPY Principal Investigator & Institution: Kang, Un Jung.; Associate Professor; Neurology; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 01-AUG-1993; Project End 31-MAR-2007 Summary: (provided by applicant): L-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay of therapy for Parkinson's disease (PD). Chronic L-DOPA therapy is limited, however, by the development of motor response complications, such as progressively shorter duration of improvement in akinesia (wearing-off) and the appearance of LDOPA-induced abnormal involuntary movements. Innovative methods of sustained and localized central nervous system (CNS) dopamine delivery may further optimize LDOPA therapy. Such methods are being explored clinically by CNS transplantation studies with fetal dopaminergic neurons and experimentally by neuronal stem cell implants and gene therapy. Our studies during the past funding cycles have defined optimal sets of genes necessary for dopamine replacement using ex vivo gene therapy
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using genetically modified fibroblasts. We also developed rat behavioral models that are relevant to the akinesia of PD patients. Using akinesia behaviors, we have noted that lesion severity has a major influence on the shortening of the response duration with minor contribution by the chronic intermittent L-DOPA therapy. Therefore, studies proposed in this continuing renewal application will determine the optimal parameters of gene therapy to improve akinesia and minimize and prevent motor response complications. We will use adeno-associated virus vectors to deliver tyrosine hydroxylase and guanosine triphosphate (GTP) cyclohydrolase 1 genes. The optimal combination of anatomical targets for gene therapy to improve akinesia will be defined by examining the effects of gene therapy delivered to basal ganglia structures, such as subthalamic nucleus, substantia nigra par reticulata, that receive dopaminergic inputs, in addition to the striatum. The optimal timing to initiate dopamine replacement gene therapy to forestall development of motor response complications will also be examined. These results will have significant implications beyond dopamine replacement gene therapy proposed here and guide other therapies such as fetal dopaminergic cell transplantation, neurotrophic factor therapy, stem cell therapy, and other CNS targeted delivery systems. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOPAMINERGIC AND BASAL GANGLIA PLASTICITY IN AGING Principal Investigator & Institution: Mcneill, Thomas H.; Professor; Neurogerontology; University of Southern California 2250 Alcazar Street, Csc-219 Los Angeles, Ca 90033 Timing: Fiscal Year 2002; Project Start 01-JUN-1991; Project End 31-MAY-2003 Summary: A basic knowledge of how we age is essential for our understanding of agerelated impairments in brain function that lead to major personal and economic problems for older citizens. In addition, changes in the brain considered part of normal aging may contribute to the onset and progression of age-related neurodegenerative diseases of the central nervous system (CNS), the classic examples of which are Alzheimer's, Huntington's and Parkinson's diseases. However, while many of the neurodegenerative diseases of the CNS have a characteristic age of onset after midlife, it is unclear what role age-related changes in the morphological, biochemical and electrophysiological properties of CNS neurons play in the onset and progression of a disease process. The proposed program project targets this gap in our knowledge of the aging brain by testing hypotheses about mechanisms of age-related changes in brain function. We propose an integrated program of basic research to examine the cellular and molecular mechanisms involved in brain aging, with particular emphasis on the substantia nigra and striatum, structures especially vulnerable in Parkinson's and Huntington's diseases. The study of reactive synaptogenesis, neuron death and functional adaptability to aging and injury represent the main areas of focus on our renewal application. Furthermore, we propose to manipulate age-related changes in dopaminergic function using chronic dietary restriction or treatment with the dopamine agonist pergolide. These studies will investigate the cellular and molecular events associated with oxidative stress in aging, with an emphasis on GFAP expression and other glial responses that we have documented in response to neurodegeneration. In addition, we will analyze the expression of several recently discovered genes, including apoJ, SCG-10, BDNF, GDNF, which seem to play key roles in processes determining cell survival and plasticity. The proposed experiments will help to understand the cellular and molecular mechanisms that lead to cell death in some regions of the aged brain and will provide the basis for the development of future therapeutic strategies aimed at the treatment of age-related neurodegenerative diseases of the CNS.
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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DOPAMINERGIC MODULATION OF WORKING MEMORY IN PD Principal Investigator & Institution: Hershey, Tamara G.; Psychiatry; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 15-JUL-2001; Project End 31-MAY-2006 Summary: (provided by applicant): The applicant is a clinical neuropsychologist with graduate training in neuropsychology and postdoctoral training in neuropharmacology and positron emission tomography (PET). The goal of this career development award is to integrate and advance these two areas of interest to answer questions about the neuropharmacological and neurophysiological basis of cognitive dysfunction in movement disorders such as Parkinson's disease (PD). This award will provide the applicant with training in the technical and theoretical issues related to using cognitive and pharmacological activation techniques in functional magnetic resonance imaging (fMRI). Long-term objectives are to address questions about the neural basis of cognitive dysfunction in movement disorders related to dopaminergic and/or basal ganglia dysfunction, such as PD, Tourette's syndrome and Huntington's disease. In addition, questions about the effects of dopaminergic treatments for these and other disorders (e.g. dystonia) on cognitive and neurophysiological functioning are also of interest. Cognitive dysfunction in these diseases, either due to the disease process itself or its treatments, can be limiting and disabling. Understanding the neurophysiologic basis for these symptoms may aid in assessing the effectiveness of current treatments or in developing better treatments. During the award period, the applicant will develop expertise in the use of fMRI, cognitive and neuropharmacological techniques to study these disorders, and will continue to hone her clinical skills in the neuropsychological assessment of movement disorders. The applicant will apply these new techniques to investigate the role of dopamine in working memory. The specific aims of the proposed studies are to test the hypothesis that 1) PD affects prefrontal cortex involvement in working memory and 2) dopaminergic modulation of working memory primarily occurs due to changes in lateral prefrontal cortical activity. To test these hypotheses, the applicant will first perform a behavioral study examining the effects of a steady-state infusion of levodopa, a dopamine precursor, on verbal and spatial working memory in PD patients and controls. The results of this study will then guide the choices of working memory tasks for an fMRl study. Subjects will be asked to perform working memory tasks before and during a steady-state infusion of levodopa. Modulation of the lateral prefrontal cortex is predicted during levodopa infusion. The degree of modulation is predicted to depend on baseline dopaminergic status (PD vs control) and the degree of memory load (low vs high). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DYNAMIC MACAQUE BASAL GANGLIA SACCADE NETWORKS Principal Investigator & Institution: Graybiel, Ann M.; Professor; Brain and Cognitive Sciences; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 04-AUG-2000; Project End 31-MAY-2005 Summary: (Adapted from applicant's abstract): The basal ganglia have been strongly implicated in the control of saccadic eye movements on the basis of clinical and experimental studies. Oculomotor defects occur in patients with extrapyramidal disorders such as Parkinson's and Huntington's disease, and lesions or inactivation of the striatum and other basal ganglia nuclei can produce such defects experimentally.
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The oculomotor zone of the striatum is centered in the caudate nucleus. This nucleus projects to the substantia nigra, pars reticulata (SNr), which in turn projects to the superior colliculus. Evidence suggests that this circuit is a release circuit for saccades. The oculomotor zone has been investigated intensively with conventional single unit recording methods in highly over-trained macaques. The results of these experiments suggest that single units in the oculomotor zone of the caudate nucleus have response properties that resemble those in saccade-related regions of the frontal cortex, including the frontal eye field (FEF), the supplementary eye field (SEF) and the dorsolateral prefrontal cortex (DLPFC). These include responses in visually guided and memoryguided tasks and in sequential saccade tasks. Nothing is yet known, however, about the ensemble activity of saccade-related neurons in the oculomotor zone of the striatum (OMZ-S), or its cortico-basal ganglia loops with the FEF, SEF and DLPFC. Nor is it known how activity is modulated in the oculomotor zone and its associated cortical loops as monkeys acquire procedural learning tasks, behavior thought to be a core function of the basal ganglia. We hypothesize that during learning neurons in the oculomotor zone of the striatum will show progressively more task-related activity and that during the overtraining period population-level coding will emerge in this oculomotor zone. We further hypothesize that temporally coordinated patterns of activity will emerge in cortico-basal ganglia loops during learning and that these will be detectable using chronic multi-unit recording methods. We propose experiments based on preliminary studies to record chronically in 1-2 week bouts from initially naive macaques as they learn procedural saccade tasks. Using multiple tetrodes, stereotrodes and conventional electrodes, we Propose to study multi-unit neural activity in the oculomotor zone of the striatum during acquisition (Aim 1), to study the functional local network architecture of the oculomotor zone during performance (Aim 2), and to study activity in cortico-basal ganglia loops with simultaneous ensemble recordings in the oculomotor zone of the striatum together with the FEF, SEF and DLPFC (Aim 3). The results obtained will have significance for understanding forebrain oculomotor control circuits and for understanding oculomotor defects in extrapyramidal disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECTS OF DBS ON POSTURE AND OROMOTOR CONTROL Principal Investigator & Institution: Horak, Fay B.; Senior Scientist and Professor; None; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-MAR-2001; Project End 31-DEC-2005 Summary: (Adapted from the Applicant's Abstract): Balance, gait, speech, and swallowing deficits are major causes of disability in patients with Parkinson's disease (PD). In many patients, these "axial symptoms" are resistant to levodopa therapy. A potential advantage of deep brain stimulation (DBS) of globus pallidus internal (GPi) and the subthalamic nucleus (STN) could be improvement of these axial motor symptoms. Our long-term goal is to determine the effects off DBS on axial motor control in order to understand the role of the basal ganglia in centrally (voluntarily) and peripherally (automatically) initiated axial movements. We hypothesize that there are multiple motor outputs from the basal ganglia with differing sensitivity to dopamine and DBS. The goal of this project is to distinguish functionally different basal ganglia control mechanisms for the axial motor system by their unique patterns of response to DBS and levodopa when used separately and when used in combination. We hypothesize that DBS will he more effective than levodopa and that STN stimulation will be more effective than GPi stimulation for axial parkinsonian symptoms. This project will take advantage of a unique opportunity to rigorously quantify the effects of
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chronic DBS in radiologically-identified human basal ganglia in a randomized, doubleblind study. These studies will quantify forces and movements in two types of postural and oromotor tasks: peripherally triggered, automatic responses to external cues and centrally-initiated voluntary movements. The specific aims are: (1) To determine how DBS affects centrally-initiated and peripherally-triggered postural control. (2) To determine how DBS affects centrally-initiated and peripherally-triggered oromotor control. (3) To investigate the interactions of DBS and levodopa treatment on postural and oromotor control. (4) To determine effects of the site (GPi versus STN) of DBS on postural and oromotor control. These experiments will quantify the efficacy of DBS and levodopa both separately and when combined for balance and oromotor deficits in patients with PD. Quantifying two types of postural and oromotor control in the same subjects will also substantially increase our understanding of the role of the basal ganglia in axial motor control. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUNCTIONAL MAGNETIC RESONANCE IMAGING OF THE BRAIN Principal Investigator & Institution: Hyde, James S.; Professor; Biophysics; Medical College of Wisconsin Po Box26509 Milwaukee, Wi 532260509 Timing: Fiscal Year 2002; Project Start 01-JUL-1995; Project End 31-MAR-2003 Summary: The central theme of this Program Project competitive renewal proposal is the fundamental development of functional magnetic resonance imaging (fMRI) into a quantitative basis of mental health. Project I proposes a testable model of fMRI contrast expressed in terms of cerebral blood flow, blood volume and metabolism. It uses a rat fMRI model as well as human subjects to probe issues of fMRI spatial resolution and temporal response and of spontaneous fluctuations in these physiological parameters. Project II addresses polymodal sensory and attentional interactions. It seeks to determine rules governing polymodal interactions using visual and auditory motion processing paradigms as an essential step in understanding sensory and attentional deficits caused by brain pathology. Project II is designed to understand how temporal information is represented in the brain. Using pharmacological probes of normal subjects and studies of patients with basal ganglia disease, this project will test the hypothesis that a unified neural system mediates both perceptual and motor timing. Project IV is built on the experimental observation that "negative" fMRI responses are most frequently seen in brain areas that have also been implicated in semantic processing. It tests the hypothesis that non-semantic tasks produce decreases in neural activity in regions normally engaged in semantic processing. If true, novel research approaches to several neuropsychiatric diseases become available. Core A, Administration, in addition to normal activities, places emphasis on coordinating development of local brain gradient and RF coil technology. Core B focuses on fMRI technology development including interactive real time fMRI at 1/5 and 3 Tesla and extension of the integrated software system AFNI developed in the previous funding period. Core C provides stimulus delivery and subject monitoring capabilities and will continue to refine the Mock scanner for acquiring behavioral and psychophysical data in a simulated MRI environment. These closely integrated initiatives seek to extend fMRI beyond simple mapping into a technique for probing the integration of diverse brain systems in order to make further progress towards the long-term goal of application of fMRI to neuropsychiatric disease and mental health. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GABA-MEDIATED ANTICONVULSANT ACTIONS AND BASAL GANGLIA Principal Investigator & Institution: Gale, Karen N.; Associate Professor; Pharmacology; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2002; Project Start 01-MAR-1984; Project End 31-AUG-2005 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENE EXPRESSION IN HIV ASSOCIATED DEMENTIA BRAIN Principal Investigator & Institution: Shapshak, Paul; Research Professor; Psychiatry and Behavioral Scis; University of Miami-Medical Box 248293 Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 15-JUL-2001; Project End 31-MAR-2005 Summary: (provided by applicant): HIV-1 infection of the brain can result in HIV-1 associated dementia (HAD) and HIV encephalitis (HIVE). HIV-infected cells release viral proteins such as envelope and tat that have direct toxic effects in the brain. Indirect effects include gene expression induced in infected and uninfected cells such as production and release of toxic molecules. The host genes that produce these toxic molecules may be placed in functional groups that include NMDA receptors, chemokines, cytokines, growth factors, their receptors, apoptosis genes, nitric oxide synthases, cell surface markers, adhesion molecules, and toxic glutamic, arachidonic, and quinolinic acid pathways. We will focus on the basal ganglia since this is a region where effects of infection have been demonstrated using brain imaging, clinical, and molecular analyses. AIDS brain tissue diagnosed with and without HAD and HIVE will be provided by the National NeuroAlDS Tissue Consortium. We will micro-dissect individual macrophage-lineage cells, astrocytes, and neurons from tissue sections using LCM to attain specificity. We will use Affymetrix High Density Gene Chip HU 95A Arrays with 12,000 human genes and ESTs to identify changed expression profile of these genes related to HIVE and HAD. Prior techniques such as Northern blots or gel shift assays were more limited in their approach. Affymetrix GeneChip Analysis Suite and GeneCluster will be used for data analysis and we will assess the statistical significance of changes in gene expression observed in each cell type by comparing the results to those obtained from random permutations of the data. We will also confirm gene expression changes using Real Time RT-PCR. In situ hybridization and immunohistochemistry will be used to determine cell specificity of target gene detection to determine the pathological significance of these genes. This exploratory R21 proposal will obtain the preliminary information needed for a larger-scale R0l study to increase the number of cases, refine and increase the number of genes analyzed, and more specifically study those genes whose expression significantly changes as a result of HAD and HIVE. Gene targeting for therapeutic intervention of HAD and HIVE will be feasible. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GENETIC ABBERATIONS IN HPRT DEFICIENCY Principal Investigator & Institution: Friedmann, Theodore; Professor; Pediatrics; University of California San Diego La Jolla, Ca 920930934 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Lesch Nyhan disease (LND) is a complex neurobehavioral disease caused by deficiency of the X-linked purine salvage pathway
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enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT). The abnormal neurological phenotype includes retardation, choreoathetosis and self-injurious behavior. The CNS defects are associated with a basal ganglia deficiency of dopamine (DA). A mouse HPRT knockout model displays a relatively normal neurological phenotype but also shows a deficiency of dopamine in the striatum. Primary cultures of midbrain neurons from HPRT-deficient mice demonstrate a reduction of dopamine levels and dopamine uptake. However, to date there has been relatively little progress toward an understanding of the mechanisms by which HPRT deficiency leads to dopamine deficiency. To identify the potential intermediary role of secondary genes functionally downstream of HPRT activity, we have used microarray gene expression analysis on commercially available MU74 oligonucleotide mouse genome chips that interrogate approximately 12,000 known genes and ESTs. In preliminary comparisons of gene expression in dissected striata from wild type and HPRT-deficient mice, we have detected reproducible changes in the expression of a small number of genes and ESTs, including those encoding translation initiation factors IF2s3 and IF3s1, genes associated with striatal dopaminergic neuron function such as sepiapterin reductase that regulates expression of the tetrahydrobiopterin co-factor of tyrosine hydroxylase, and casein kinase I-epsilon that phosphorylates DARPP-32, the principal striatal target for dopamine function. We have also found preliminary evidence for dysregulation of a number of other cDNAs and ESTs of still uncertain relevance to HPRT deficiency. We propose now to complete a more thorough genome characterization of normal and HPRT-deficient mice, to examine the functional effects of aberrant expression of these genes in cultured midbrain and striatal DA neurons and in transgenic and knockout mice. We also plan to determine the biochemical and neurotransmitter effects of genetic correction of these functions by gene transfer techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC REGULATION OF TELENCEPHALON DEVELOPMENT Principal Investigator & Institution: Rubenstein, John L.; Professor; Langley Porter Psychiatric Institute; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): The central tenet of this proposal is that the Dlx family of homeobox genes is essential for regulating the differentiation and function of forebrain GABAergic neurons. Accordingly, I suggest that the Dlx genes are required for controlling the development, and perhaps the function, of intemeurons in the cerebral cortex, and projection neurons in the basal ganglia. Therefore, understanding the functions of the Dlx genes should yield insights into the roles of GABAergic neurons in forebrain neural systems, and may provide insights into disorders of the forebrain due to defects in GABAergic neurons. The experiments described herein use standard and conditional genetic methods to alter the expression of the Dlx genes in developing mice. These methods will allow us to study the effects of deleting individual and/or multiple Dlx genes on the development and function of forebrain GABAergic neurons. In addition, we will investigate the effects of ectopically expressing the Dlx genes. These studies have implications for understanding the genetic pathways that regulate the specification, differentiation and function of forebrain GABAergic neurons, and have implications for understanding the molecular bases of human disorders of GABAergic neurotransmission. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GLUTAMATE IN PARKINSON'S DISEASE Principal Investigator & Institution: Greenamyre, John T.; Professor; Neurology; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JAN-1995; Project End 31-MAY-2004 Summary: (Verbatim from the applicant's abstract) Loss of striatal dopaminergic innervation in Parkinson's disease (PD) is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. Prominent among the neurotransmitters; altered in PD is the glutamatergic system. For example, the glutamatergic pathways from subthalamic nucleus to the internal segment of globus pallidus and the substantia nigra pars reticulata become overactive after nigrostriatal dopamine depletion. Moreover, there is increasing evidence that corticostriatal projections also become overactive in models of PD. Our laboratory and others have shown that this glutamatergic overactivity has clinically relevant functional consequences and contributes importantly to the pathophysiology of parkinsonian signs and symptoms. Stereotactic or systemic blockade of glutamate receptors has remarkable antiparkinsonian and antidyskinetic effects in experimental animals and in patients with PD. We propose to continue to study in a systematic fashion the effects of various classes of glutamate antagonists in MPTP-treated parkinsonian monkeys, and to examine functional changes in the glutamatergic system in this model of PD. In so doing, we expect to identify viable pharmacological targets for therapeutic intervention in PD. Specifically we propose to: 1. Continue to examine the antiparkinsonian efficacy of a wide range of glutamate antagonists in MPTP-treated parkinsonian monkeys 2. Use various combinations of glutamate antagonists, individually demonstrated in Specific Aim 1 to be efficacious, and test for additive or synergistic actions. 3. Compare the development and severity of dyskinesias in de novo parkinsonian monkeys treated chronically with (1) levodopa alone, or (2) a combination of levodopa and an NMDA antagonist. 4. Examine the antidyskinetic efficacy of NMDA and AMPA receptor antagonists and glutamate release inhibitors in monkeys with established levodopainduced dyskinesias. 5. Use immunocytochemistry and immunoautoradiography to map changes in basal ganglia glutamate receptors in MPTP-treated monkeys, and to use in vivo [3CH]dihydrorotenone binding to map metabolic changes in these brains. By using techniques ranging from measurement of receptor subunit protein levels to preclinical testing of drugs in parkinsonian monkeys, we plan to take a comprehensive approach to the study of glutamate in Parkinson s disease. It is anticipated that our studies will result in an improved understanding of the pathophysiology of this disorder and lead directly to improved therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: GP120-MEDIATED CELL DEATH IN THE BASAL GANGLIA Principal Investigator & Institution: Nosheny, Rachel L.; Neuroscience; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2006 Summary: (provided by applicant): More than 50% of human immunodeficiency virus type 1 (HIV-1) infected individuals experience neurological and psychiatric problems that are collectively termed the AIDS Dementia Complex (ADC). The current global AIDS crisis highlights the need for therapeutic strategies to treat ADC. A wealth of experimental data has implicated glycoprotein gpl20, an HIV-derived envelope protein that facilitates viral entry into cells, in the cell death associated with ADC. Clinical observations of ADC patients, in vitro characterization of cell types vulnerable to gp 120
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neurotoxicity, and preliminary in vivo data in our laboratory suggest that basal ganglia dysfunction, especially of the nigro-striatal pathway, is integral to the neurological manifestations in ADC. Neurotrophic factors are naturally occurring proteins that are essential for brain development and maintenance of neuronal populations affected in ADC. The proposed experiments will examine the hypothesis that gp 120 causes cell death in the basal ganglia and that neurotrophic factors can protect against gp 120mediated cell death. This neuroprotection in turn may limit neurological complications associated with HIV infection in the brain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEMISPHERIC SPECIALIZATION AND COMMUNICATION Principal Investigator & Institution: Hopkins, Williams D.; None; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-JUN-2002; Project End 31-MAY-2005 Summary: (provided by applicant): The long-term objectives of the proposed studies are to understand the role that early environment plays in the development of asymmetries in manual gestures and facial expressions and their relationship to different structures of the brain. In the proposed research, behavioral studies on functional asymmetries in hand use for gestural communication and facial expressions used with referential vocalizations will be correlated with neuroanatomical asymmetries as assessed by magnetic resonance imaging (MRI). Specifically, whether hand use for gestures represents a unique functional asymmetry or whether it reflects a general asymmetry for all motor functions will be assessed by comparing handedness indices for gestures compared to motor tasks with similar situational demands. In another series of experiments, the influence on vocal communication on the expression of hand use for referential gestures will be assessed to determine whether the vocal signals enhances or inhibits the magnitude of asymmetries in communicative behavior. In a third set of experiments, asymmetries in facial expressions that made by chimpanzees that have a referential function will be compared to asymmetries in facial expressions that are not accompanied by the use of a referential vocalization. Finally, asymmetries in gestural communication and facial expressions will be correlated with asymmetries in the brain from specific regions of interest including the planum temporale, Brodmann's area 44, the motor/hand area of the precentral gyrus, cingulate gyrus and basal ganglia. Of specific interest in all analyses will be, the comparison of chimpanzee subjects that have been reared by human compared to those reared by chimpanzees. This comparison will allow for determination of how human environments and communication systems alter the development of communicative behavior and the cerebral organization of chimpanzees. Overall, the proposed research will lead to a better understanding of factors which influence the development of laterality in the central nervous systems and behavioral and communicative correlates of these asymmetries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HEPATIC NEUROCHEMISTRY
ENCEPHALOPATHY--NEUROPSYCHOLOGY
&
Principal Investigator & Institution: Thomas, Michael A.; Associate Professor; Radiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 05-AUG-1999; Project End 31-JUL-2004
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Summary: (Verbatim from the Applicant's Abstract) Hepatic Encephalopathy (HE) is a well-recognized complication of cirrhosis. These patients display a variety of neuropsychological deficits as well as clinical and serum ammonia abnormalities. Subclinical hepatic Encephalopathy (SHE) is a subtler accompaniment of cirrhosis that is associated with neuropsychological abnormalities without significant neurologic findings such as asterixis. Although neuropsychological tests are the current standard for diagnosing SHE, the results are non-specific and reveal little about the underlying neurochemical processes. Cerebral Magnetic Resonance Spectroscopic (MRS) metabolic alterations and MRI signal abnormalities in the basal ganglia reveal a relationship between neuropsychological functioning and biochemical abnormalities found in patients with SHE. This study will involve collaboration among hematologists, radiologists, psychiatrists, MR physicists and neuropsychologists. We will identify a total of 60 liver failure patietns who have SHE and compare them to 60 healthy control subjects. These patients and healthy controls will undergo clinical assessment by hepatologists and neuropsychiatric evaluation by psychiatrists. Subsequently, they will undergo a comprehensive series of neuropsychological tests to characterize the nature of their neurocognitive deficits. Following these tests, all subjects will undergo MR Imaging and Spectroscopic (MRI/MRS) examinations. We aim to use 1H MRS to meare and compare absolute cerebral metabolite levels of myo-inositol, choline, and glutamine/glutamate in the frontal lobe, parietal lobe and basal ganglia of a matched group of SHE patients and healthy controls. The resulting MRS and MRI data will be quantitatively analyzed and correlated with the results of neuropsychological testing and clinical examination. Multivariate methods and correlational analysis will be used to test hypotheses regarding differences between SHE patients and controls. We hypothesize that myo-inositol will be decreased, glutamine/glutamate will be increased and choline will be decreased in patietns with SHE. We propose that these underlying biochemical abnormalities will be correlated with clinical, neuropsychiatric and neuropsychological aspects of SHE. If these relationships are found, they will provide an improved biochemical understanding of the underlined aspects of SHE as characterized y clinical and neuropsychological testing. This enhanced understanding of pathophysiology will improve our ability to diagnose and treat this condition, resulting in improved patient outcomes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INFLUENCE OF THE BASAL GANGLIA ON CEREBELLAR ACTION Principal Investigator & Institution: Gibson, Alan R.; Staff Scientist; St. Joseph's Hospital and Medical Center 350 W Thomas Rd Phoenix, Az 850134409 Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Diseases affecting the basal ganglia produce a variety of movement deficits, and these deficits are often totally disabling. Parkinson's disease, which affects about 1.5 million Americans, is a basal gangliar disease that leads to tremor, decreased spontaneous movement and slowness of voluntary movement. Drug treatment of Parkinson's disease with L-DOPA is only partially effective in relieving the motor symptoms of the disease, and prolonged drug treatment leads to severe side effects such as uncontrollable involuntary movements. Deep brain stimulation at specific sites in the basal ganglia can provide effective relief of Parkinson symptoms. Neither drug treatment nor deep brain stimulation restores damaged neural circuitry in the basal ganglia. Therefore, it is likely that these therapies prevent abnormal basal gangliar output from disrupting processing in other structures related to movement control. One major neural structure related to movement control is the
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cerebellum, but there are no direct connections between the cerebellum and the basal ganglia. We have discovered that disrupting activity in the cat red nucleus, which connects cerebellar output to the spinal cord, can produce motor symptoms that are strikingly similar to those of Parkinson's disease. The general hypothesis underlying this proposal is that motor deficits produced by basal gangliar disease are mediated by pathways that allow basal gangliar output to disturb processing in structures related to the cerebellum. Specifically, we hypothesize that basal gangliar output from the cat entopeduncular nucleus affects activity of cells in zona incerta, which affects activity of cells in the red nucleus. Our experiments will: 1. Identify regions in the related nuclei that contain cells related to forelimb movement. 2. Determine how these forelimb regions affect movement with activation and inactivation by injection of receptor antagonists. 3. Develop an acute and chronic cat model of basal gangliar disease to test critical aspects of the hypothesis. 4. Identify additional brainstem pathways that allow basal gangliar output to influence cerebellar circuits. The results will provide a deeper understanding of how the basal ganglia and cerebellum interact to control limb movements and will lead to new approaches for the treatment of movement disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INTEGRATIVE FUNCTIONS OF PRIMATE PREFRONTAL CORTEX Principal Investigator & Institution: Miller, Earl K.; Picower Professor of Neuroscience; Brain and Cognitive Sciences; Massachusetts Institute of Technology Room E19-750 Cambridge, Ma 02139 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-JAN-2007 Summary: "Divide and conquer" seems to dominate many neural analyses: There are specialized systems for analyzing different types of information. Cognition requires synthesizing their results. To plan and execute complex, goal-directed behaviors we must learn "the rules of the game": predictive relationships between disparate sensory events, environmental context, the possible actions and consequences. This depends on brain systems specialized for learning and memory: the prefrontal cortex (PFC), basal ganglia (BG) and hippocampal systems (HS). Damage to any of these systems, or their disconnection, impairs rule learning. Previous studies have shown that neural correlates of acquisition and/or representation of concrete (specific) rules and higher-level abstract rules (general principles) are prevalent in the PFC, a brain region central to rule-based behaviors. But our understanding is limited by our lack of knowledge about the respective contributions of, and PFC interactions with, the other critical systems: the BG and HS. The main goal of this project is to provide that knowledge. We plan to simultaneously study neural activity from up to 28 electrodes implanted these systems while monkeys larn and follow concrete rules )conditional visuomoter associations between an object and a saccade direction) and follow abstract rules (matching and nonmatching rules applied to new stimuli). This will afford a precise assessment of the respective contributions of the PFC, BG, and GS to complex goal-directed behaviors and insight into the underlying neural circuitry. Our specific aims are: 1. To compare and contrast the neural representation of concrete rules in the PFC with anatomically and functionally-related systems (BG and HS). 2. To assess the relative contributions of PFC, BG and HS to rule acquisition by comparing neural correlates of their learning. 3. To compare and contrast the neural representation of abstract rules in the PFC with the BG, and HS. As rule learning is fundamental to all higher-order behavior, data from this project has the potential to impact on our understanding of a wide range of behaviors and human and human disorders. The ability to glean rules and principles from experience is disrupted in a variety of neuropsychiatric disorders such as autism and
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schizophrenia. By identifying brain structures important for these abilities, discerning their relative roles, and uncovering their neural mechanisms, we can open a path to drug therapies designed to alleviate their dysfunction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LEARNING IN THE HUMAN MOTOR CORTEX Principal Investigator & Institution: Ashe, James; Associate Professor; Neuroscience; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2004; Project Start 20-APR-2000; Project End 31-MAR-2008 Summary: (provided by applicant): The long-term objective of this proposal is to understand how the brain learns and control movement sequences. As Lashley recognized more than half a century ago, much of our behavior, from the performance of organized movements to the ability to use language, is based on our capacity to detect, learn, and produce sequences. In the current proposal, we use variants of the serial reaction time (SRT) task and functional imaging in human subjects to examine the neural substrates responsible for learning the fundamental structure of movement sequences, the brain areas responsible for modulating learning through reward and punishment, and the extent to which the brain uses similar strategies for learning temporal and spatial sequences. We will test the following hypotheses. (1) During sequence learning cortical motor areas detect and learn transitions from one element to the next, while the basal ganglia encode the whole structure of sequenced movements. (2) Reward and punishment have direct but differential effects on motor sequence learning and this will be reflected by proportional changes in the activity of the basal ganglia. (3) Learning sequences of temporal intervals will engage a similar set of brain areas to those involved in learning spatial sequences and will not involve the cerebellum. Impairment in the ability to produce sequences is an important component of the disability experienced by patients with Parkinson's disease. The work outlined here will provide a fundamental understanding of these disabilities and may lead to the development of strategies for rehabilitation and treatment of these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISM OF SENSITIZATION TO COCAINE Principal Investigator & Institution: Angulo, Jesus A.; Hunter College Room E1424 New York, Ny 10021 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MECHANISMS OF ADULT SONG PLASTICITY IN BENGALESE FINCHES Principal Investigator & Institution: Brome, Clinton R.; Physiology; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-OCT-2005 Summary: (provided by applicant): Vocal learning and control in songbirds, a system with many striking parallels to human speech, is used here as a model system to address general issues in the sensorimotor learning and control of complex behaviors. These issues include the production of sequences of stereotyped motor acts, the adaptive correction of errors in a motor plan, and the role of a basal ganglia circuit in adult motor
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control and plasticity. In the first part of this work, altered auditory feedback will be used to probe how this feedback is involved in both the on-line control of song production and in longer-term adaptive corrections to motor output. Specifically, mechanisms involved in the deterioration of song sequence under conditions of disrupted feedback will be investigated, as will the mechanisms involved in the active maintenance of adult song. In the second part, lesions in the "anterior forebrain pathway" (AFP), a basal ganglia-forebrain circuit strongly implicated in juvenile song learning, will be used to investigate the role of this circuit in adult song plasticity and production. These experiments will further our understanding of the avian song system and of the role of sensory feedback in motor learning and control, both generally and with particular relevance to human speech. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: METHAMPHETAMINE NEUROTOXICITY
AND
HIV
PROTEIN-INDUCED
Principal Investigator & Institution: Maragos, William F.; Associate Professor; Neurology; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-DEC-2005 Summary: Several lines of evidence indicate that the basal ganglia are highly susceptible to infection with the human immunodeficiency virus (HIV). However, the pathogenesis of basal ganglia dysfunction is not well understood. Patients with HIV infection often abuse drugs such as methamphetamine, a drug that is well known to also cause long-term structural and functional changes to the basal ganglia. There is now mounting evidence that "virotoxins" (viral products released from infected cells) and methamphetamine share a common mechanism, which leads to neuronal damage. Two such products are the HIV proteins gp120 and Tat. In this proposal, we will examine the degree of synergy between these virotoxins and methamphetamine by determining the severity of damage they cause to the dopaminergic system in vivo and to human cortical neurons in vitro. To identify common mechanisms that lead to neuronal dysfunction and ultimately, to cell death, we will also examine two pathophysiological processes that contribute independently to virotoxin and MA toxicity, namely reactive oxygen species and the cytokine TNF-alpha. In studying these two processes, we will 2) measure production of compounds of interest (e.g. reactive oxygen species and TNFalpha) and determine the efficacy of a variety of inhibitors on neurotoxicity. To accomplish these goals, we will assess the effects of intrastriatal injections of virotoxins in animals treated with methamphetamine and in vitro in human cortical neurons where cell types can be manipulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: RECEPTORS
METHAMPHETAMINE
TOXICITY
AND
STRIATAL
NMDA
Principal Investigator & Institution: Chapman, David E.; Pharmacology and Toxicology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-OCT-2002; Project End 31-JUL-2003 Summary: (provided by applicant) Substituted amphetamines, such as methamphetamine (METH), produce long-lasting, partial loss of central monoamine systems. The postsynaptic consequences of the such loss on basal ganglia function, however, are less well known. Preliminary data from our laboratory suggest that the expression of the NR2A subunit of the NMDA receptor (NMDAR) is increased
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throughout the striaturn 3 weeks following a neurotoxic regimen of METH. The NMDAR is comprised of an NR1 subunit and any of four NR2 subunits (NR2A-D), which confer different properties to the receptor. Whereas the NR2B subunit is expressed at uniform levels throughout striaturn the NR2A subunit, displays greater expression laterally. We have shown that the greater NR2A subunit expression in lateral striatum is associated with NMDAR-mediated excitatory postsynaptic currents (EPSCs) with faster kinetics than those in medial striatum. Others have demonstrated and inability to induce NMDAR-dependent long-term porentiation (LTP) in dorsolateral, but not dorsomedial, striatum. Thus, the level of expression of the NR2A subunit determines NMDAR function in striatum. Thus, this proposal will test the hypothesis that increases in NR2A subunit expression induced by a neurotoxic regimen of METH will alter NMDAR function. This will be accomplished by completing the following specific aims: A) Determine the functional impact of METH-induced changes in NR2A subunit expression on NMDAR-mediated EPSCs in dorsolateral and ventromedial striatum. B) Examine the functional consequences of METH-induced changes in the monoamines and NR2A subunit expression on striatal LTP. The results of these studies will further elucidate postsynaptic changes associated with METH neurotoxicity, and will provide molecular insight into the behavioral and cognitive alterations which ensue a neurotoxic insult induced by METH. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR BASIS OF SYNDROMIC RETINITIS PIGMENTOSA Principal Investigator & Institution: Hayflick, Susan J.; Associate Professor; Molecular and Medical Genetics; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: The goal of this project is to isolate and characterize the gene for a form of syndromic retinitis pigmentosa (RP), called Hallervorden-Spatz syndrome (HSS) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and early, rapidly progressive pigmentary retinopathy. This autosomal recessive disorder of childhood includes extrapyramidal dysfunction with iron accumulation in the basal ganglia. Though lipid peroxidation is an hypothesized mechanism leading to the HSS phenotype, no knowledge exists of the molecular or biochemical defect. We propose a molecular genetic approach to understanding this syndromic form of RP. Our specific aims are to 1) identify the gene for HSS, designated NBIA1 (Neurodegeneration with Brain Iron Accumulation, type 1) by completing the physical map of the critical region, identifying and screening candidate genes, and demonstrating deleterious mutations; 2) develop the molecular diagnosis of HSS using mutation studies and genotype-phenotype correlation; 3) characterize the HSS gene and its protein product at the tissue, cellular, subcellular and molecular levels using homology to model organisms, sequence analysis, histopathology, immunohistochemistry and studies of tissue expression patterns; and 4) isolate the murine homolog of the HSS gene and develop a mouse model for HSS in order to study its pathophysiology. Knowledge about the HSS gene will allow molecular diagnosis in individuals suspected to have this disease. As well, prenatal diagnosis of this fatal condition will be feasible. By delineating the pathophysiologic process in HSS, we may begin to develop rational therapies, which may be of benefit in treating other forms of RP, as well. Rare diseases often illuminate the mechanisms at work in common, related disorders. An advantage to studying syndromic RP is that the pleiotropic manifestations provide a context to help delineate the mechanism of retinopathy. The HSS gene is not retina-specific, and a defect in it must account for rod photoreceptor degeneration as
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well as regional brain iron accumulation. Furthermore, since defects in this non-retinaspecific process may cause other forms of syndromic and isolated RP and may be integral in disorders of lipofuscin accumulation, including aging macular degeneration, identification of the HSS gene may lead to greater understanding of RP as well as the macular dystrophies associated with senescence. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MOLECULAR ETIOLOGY OF EARLY ONSET TORSION DYSTONIA Principal Investigator & Institution: Breakefield, Xandra O.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 15-JAN-1999; Project End 31-DEC-2002 Summary: Torsion dystonia is one of the most common and least well understood of movement disorders in humans. Affected individuals manifest contracted, twisting postures due to abnormal neurotransmission of the basal ganglia. This Program is directed towards elucidation of neuronal dysfunction in the early onset form of dystonia, which commences in childhood and can be completely disabling. The DYTl gene responsible for this condition is inherited in an autosomal dominant manner with low penetrance and has been recently cloned by our group. Most cases of this disease are caused by loss of a glutamic acid residue in the carboxy terminus of a novel ATPbinding protein termed torsinA. This gene is expressed selectively and at high levels in dopaminergic neurons in the substantia nigra. TorsinA defines a new gene family with distant relationship to the heat shock/Clp proteins. Our hypothesis is that defects in this protein underlie susceptibility which can lead to diminished release of dopamine into the striatum and, in turn, to altered modeling of neuronal circuitry in the basal ganglia during childhood development. The resulting imbalance in neurotransmission would then affect processing of motor information in this critical region of the brain. Studies are designed to elucidate the role of members of the torsin gene family in this and other forms of dystonia, and to identify other genes which may affect penetrance by linkage and mutational analysis. Brain tissue from human controls and affected individuals, as well as transgenic knock-in mice, will be examined by immunocytochemistry and in situ hybridization to elucidate changes in the distribution and density of proteins involved in neurotransmission, including D1 and D2 receptors. The transgenic mice will also be evaluated for alterations in the development of neuronal connections in the basal ganglia, in behavior and in response to stress. The intracellular distribution of torsinA and the functional effects of the mutant protein will be assessed in cultured dopaminergic neurons and model neural system using immunocytochemistry and a helper virus-free amplicon vector delivery of normal and mutant genes. Cells will be evaluated for functions related to other members of the heat shock/Clp family, including response to heat shock, uptake and release of dopamine, and mitochondrial function. These studies capitalize on the recent identification of the DYTl gene to understand the molecular etiology of early onset torsion dystonia, to elucidate developmental and stress- related plasticity in the basal ganglia, and to provide insights into therapeutic intervention. Given the apparent involvement of dopaminergic neurons in dystonia and Parkinson's disease, these studies should also provide insight into the latter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOTOR ACTIONS OF CANNABINOIDS IN A PARKINSONS MODEL Principal Investigator & Institution: Sanudo-Pena, Clara M.; Psychology; Brown University Box 1929 Providence, Ri 02912 Timing: Fiscal Year 2002; Project Start 01-JAN-2000; Project End 31-MAR-2002 Summary: The hallmark of Parkinson s disease is a dopamine deficiency in the basal ganglia due to degeneration of dopaminergic neurons in the substantia nigra pars compacta. Because of this, the physiology of the neurotransmitter dopamine in the basal ganglia has been extensively studied. However, none of the current models of basal ganglia function includes the novel cannabinergic neurotransmitter system. The recent cloning and mapping of a nervous cannabinoid receptor unveiled high levels of cannabinoid receptors in the basal ganglia where they are as abundant as the receptors for dopamine. Furthermore, cannabinoid receptor levels in the output nuclei of the basal ganglia, the globus pallidus and the substantia nigra pars reticulata, are the highest in the brain. In recent studies we have described a major modulatory role of cannabinoids in the basal ganglia where they act on both major excitatory (subthalamic) and major inhibitory (striatal) inputs to basal ganglia output nuclei. Cannabinoids block the activation of either input, and the effect observed would be to return the system to basal levels of activity. A complex interaction between the cannabinoid and the dopaminergie system was also observed, blocking each others effects in intact animals and synergizing in the 6-OHDA model. The major modulatory action of cannabinoids in the basal ganglia counteracting both the major source of excitation and the major source of inhibition depending on their level of activity is relevant to Parkinson s disease where the subthalamic nucleus becomes hyperactive. This proposal aims to determine wether cannabinoids could be used alone or in conjunctive therapy with ineffective levels or low doses of dopaminergic drugs to counteract the motor impairments induced by degeneration of the dopaminergic innervation of the basal ganglia. Behavioral, biochemical, and physiological studies will be conducted in parallel to test this possibility. It will also help integrate the cannabinergic system with the current knowledge of basal ganglia physiology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: MOTOR LEARNING IN PARKINSON'S DISEASE Principal Investigator & Institution: Ghilardi, Maria-Felice M.; Ctr for Neurobiology Behavior; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 30-SEP-1997; Project End 31-JAN-2003 Summary: (provided by applicant): The specific aims of the original proposal were: 1. To determine the effect of Parkinson's disease (PD) on the learning of spatial and temporal features of motor learning tasks, compared to a normally aging population. 2. To test the hypothesis that the deficits in motor learning in PD result from the altered function of specific cortical and subcortical networks whose expression correlates with task performance in age-matched controls. 3. To assess the effect on motor learning of new therapies, such as pallidal ablation and pallidal stimulation. Over the past two and a half year, we have made extensive progress in accomplishing these aims, as described in Progress Report and in the publication track record. In this competing continuation application, we plan to complete the initial research and educational aims and to extend our work. Specifically, we will pursue the following aims: 1. To study the effects of DBS and levodopa administration on motor learning in PD. We have shown that aspects of motor learning are defective in the earliest stages of PD and are associated with
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abnormal brain organization. Preliminary data indicate that these abnormalities are not rectified by levodopa, but, GPi DBS can improve sequence learning and increase activity in brain regions normally involved in this process. Here we ask if STN DBS (which drives GPi and other structures mediating simple and complex motor behavior) can improve performance in PD by modulating the brain circuits involved in sequence learning, similarly to GPi DBS. PET recordings during motor tasks will be conducted in a group of PD patients with STN DBS, a group with GPi DBS, and a group treated with levodopa infusion in on and off conditions. Brain network expression and performance will be compared across groups and conditions. 2. To characterize the progression of motor and cognitive dysfunction in PD. We found that PD patients in stage I and 11 require longer time and need to recruit more brain areas to learn a motor sequence. Here we ask how performance and brain network activation change in relation to disease progression. In this longitudinal study, we will also evaluate changes in acquisition of motor skills other than sequence learning, such as adaptation to new reference frames or novel inertial configuration. We will use tasks we have recently developed and tested in a population of young normal subjects. We will ask the following questions: Which are the normal brain networks involved in the different types of learning? Are they independent or share some common bases? Does their expression change in PD patients in early stages? Does brain network expression in PD change with disease progression? These studies psychophysical and imaging studies will be conducted in the group of PD patients and age-matched controls we have tested in the previous grant period. 3. To study motor learning and execution in hyperkinetic basal ganglia disorders. Studies with "F-fluoro-deoxyglucose (FDG) and PET have demonstrated an abnormal metabolic network in clinically non-manifesting carriers of Idiopathic Torsion Dystonia (ITD) DYT I gene. In preliminary studies, we have found that motor sequence learning may be impaired in these same gene carriers. We plan to complete the psychophysical studies in non-manifesting DYTI carriers and to assess the effect of GPiDBS on rcbf in affected DYTI patients. Specifically, we will ask the following questions: Will non-manifesting DYTI carriers show motor learning and network activation abnormalities that parallel their resting metabolic abnormalities? Will non-manifesting DYT I carriers and dystonic patients show differences in motor learning and network activation? By comparing rcbf before and during pallidal stimulation, we will determine how altering pallidal function affects the expression of activation patterns subserving motor learning in ITD. Overall, these studies will provide the bases for a comprehensive understanding of basal ganglia and related cicuitry in motor learning and execution, as well as for the development of new therapeutical strategies for basal ganglia disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: MRSI OF FRONTOSUBCORTICAL CIRCUITS IN BIPOLAR DISORDER Principal Investigator & Institution: Deicken, Raymond F.; Associate Professor; Northern California Institute Res & Educ 4150 Clement Street (151-Nc) San Francisco, Ca 941211545 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2005 Summary: (provided by applicant) Developing evidence strongly suggests that bipolar disorder involves localized abnormalities in specific brain structures that participate in fronto-limbic-subcortical circuits regulating mood. The specific structures include the prefrontal cortex, anterior cingulate cortex, thalamus, basal ganglia, amygdala hippocampus, and cerebellum. There is clearly a need for systematic study of these structures in bipolar disorder to determine the magnitude and extent of regional
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neuropathology, which may be too subtle to reliably detect by present quantitative MRI measurements of tissue volume alterations. Subtle neuronal loss or damage has been shown to be readily detectable by proton magnetic resonance spectroscopy (1 H MRS I) measures of N-acetylaspartate (NAA), a neuronal and axonal marker and a reliable indicator of neuronal integrity. Therefore, this proposal will utilize high resolution MRI together with 'H MRSI to determine if there is reduced NAA, with or without tissue volume loss, in the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, caudate, putamen, hippocampus, and cerebellar vermis in bipolar disorder. MRI derived tissue volumes will be utilized together with NAA and choline measures to make preliminary inferences about regional neuropathologic changes such as neuronal dysfunction, neuronal loss (with or without gliosis), developmental hypoplasia, and synaptic/dendritic pruning failure. Second, this proposal will examine NAA measures in normal appearing white matter (NAWM) and white matter signal hyperintensities (WMSH) of the prefrontal white, subcortical, and periventricular white matter regions. White matter NAA reductions will be interpreted as evidence for axonal loss or dysfunction and evidence for compromised integrity of white matter pathways. Third, this proposal will determine if there is increased NAA. with or without increased tissue volumes, in the thalamus and amygdala in bipolar disorder. Increased NAA and/or increased tissue volumes will be interpreted as evidence for possible increased neuronal number or interneuronal neuropil. Fourth, this proposal will determine if the magnitude and/or extent of regionally specific NAA alterations is different in bipolar I compared to bipolar II disorder. Finally, this proposal will determine if longer illness duration and greater illness severity (defined as a greater number of lifetime hospitalizations for mania or depression) result in more severe brain pathology as measured by the magnitude of regionally specific NAA alterations. Determining whether the neuropathology in different brain regions is a result of progressive damage to the brain over time will have important implications for treatment interventions in binpolar disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEURAL BASIS OF DEPRESSION VULNERABILITY Principal Investigator & Institution: Shumake, Jason D.; Zoology; University of Texas Austin 101 E. 27Th/Po Box 7726 Austin, Tx 78712 Timing: Fiscal Year 2002; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): The proposed studies will investigate the neural substrates mediating susceptibility to depression in a genetic rat model. Our recent work with the congenitally helpless rat has revealed a pattern of metabolic abnormality in prefrontal cortex (PFC) and anterior cingulate cortex (ACg) that strongly parallels PET and fMRI findings from depressed humans. These rats also appear to have another, much larger, abnormality localized to the paraventricular hypothalamic nucleus (PVH). Based on these results, we seek to further investigate the role of brain regions related to the hypothalamic-pituitary-adrenal axis in congenitally helpless rats. Four specific aims are proposed: 1) Extend metabolic mapping of the congenitally helpless rat brain to regions that provide regulatory input to the PVH (hippocampus, septal area, bed nucleus of the stria terminalis), regions related to monoaminergic function (ventral tegmental area, raphe nuclei, habenula), and other regions implicated in emotional behavior (amygdala, basal ganglia, periacqueductal gray). 2) Test the hypothesis that the PVH metabolic abnormality is related to increased production of corticotropinreleasing hormone (CRH) by performing in situ hybridization for CRH mRNA. 3) Test the hypothesis that elevated CRH secretion will cause metabolic abnormalities in PFC,
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ACg, and other regions similar to those identified in the congenitally helpless rat by chronically administering CRH to normal rats, followed by metabolic brain mapping. 4) Identify brain regions linked to depression remission by administering an antidepressant (fluoxetine) to congenitally helpless rats and determining its effect on regional brain metabolism, CRH mRNA, and behavioral outcome measures. The collective results should help to integrate the roles of the hypothalamus, frontal cortex, and serotonin system in depression and its treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEURAL BASIS OF VOCAL LEARNING Principal Investigator & Institution: Doupe, Allison J.; Professor; Laboratory Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-JAN-2001; Project End 31-DEC-2005 Summary: The long-term goal of this research is to understand the neural basis of learning and memory, especially how the brain learns complex motor behaviors, guided by sensory information. Vocal learning in songbirds provides a useful model system for this purpose, with special relevance to human speech learning. Songbirds learn to produce a copy of a previously memorized tutor song during a period of "sensorimotoi" learning, in which they use auditory feedback of their own voice to refine their vocal output until it matches the memorized song. The work proposed here focusses on a particular part of the system of brain areas devoted to song learning and production, a specialized cortical-basal ganglia circuit known as the anterior forebrain pathway (AFP), because it plays a crucial but illunderstood role both in song learning and in adult vocal plasticity. Moreover, cortical-basal ganglia circuits, which are well conserved evolutionarily, are thought to function in motor and reinforcement learning in many vertebrates, and to be one critical site of dysfunction in a number of neuropsychiatric disorders. Because the songbird AFP is a discrete cortical-basal ganglia circuit controlling a specific behavior, it may prove a particularly tractable system for elucidating the very general functions of such pathways. both normally and in disease. The AFP develops song-selective auditory responses that could participate in the auditory evaluation of song during learning, and shows motor-related activity during singing, but how these sensory and motor responses relate to each other is not clear. Activity in this circuit is also extremely variable from trial to trial, raising the question of how it could reliably encode information or guide song. With simultaneous recordings from multiple neurons in the output nucleus of the AFP, LMAN, during both singing and song playback, the first aim will test the hypothesis that the AFP encodes relevant song- and singing-related information in the form of a distributed, "population" code. A further hypothesis is that specific patterns of AFP neural activity are critical for normal song development, perhaps guiding the formation of connections in the vocal motor nucleus RA. This will be tested with simultaneous recordings of neurons in both LMAN and RA, so that the covariance of their activity and how it relates to vocal output can be analyzed. LMAN-RA interactions will be studied first in normal birds at different stages of learning, and then after experimental disruptions of the pattern of activity in the AFP, in ways that will shed light both on normal synaptic processing within this circuit as well as on how it influences the song motor pathway. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEURAL CONTROL OF TRAINED MOVEMENT Principal Investigator & Institution: Thach, W Thomas.; Professor of Neurobiology & Neurology; Anatomy and Neurobiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-SEP-1977; Project End 31-MAY-2008 Summary: (provided by applicant): MAJOR GOALS are to study the roles of the cerebellum and basal ganglia in adapting, learning and storing adjustments of eye-hand coordination. Gaze will be perturbed with laterally displacing prisms (project #1) and with shift of the visual target (project #2 ) to see how monkeys adjust their reaching to visual targets. Two types of adjustment are distinguished, leaming and adaptation. In leaning, a monkey stores two gaze-reach calibrations, and can call each up immediately if it knows each condition. In adaptation, there is only one stored gaze-reach calibration, which must be adjusted back and forth by practice. Project # 1 examines whether the cerebellum and basal ganglia are both necessary for storing learned gaze-reach calibrations. Monkeys will have two gaze-reach calibrations: 1) reaching to and touching a visual target without prisms, in which eyes and reach are aligned, and 2) learned reaching to and touching a visual target with prisms, in which eyes and reach are divergent. Neurons in cerebellar cortex, deep nuclei, and globus pallidus pars interna will be recorded from then inactivated to see if the learned gaze-reach adjustment is abolished. Project # 2 asks how the cerebellar cortex, inferior olive, and parvocellular red nucleus are involved in adapting and learning to touch a visual target that has shifted in mid-reach. At the start of each block of adaptation shift trials, the visual target will shift mid-reach in a novel direction, and continue each trial to shift in that direction for the rest of the block. The monkey must adapt in order to touch the target at its shifted novel location. Then the monkey will have a block of no-shift trials, and must then dis-adapt in order to hit the target where it initially appears. During learning shift trials, the target will shift in a direction that is fixed and therefore predictable throughout the block and all such blocks of trials. The monkey will be informed that this is the learned shift condition and thus can learn it, in addition to the no-shift condition. This project focuses on the problem of how subjects adapt and learn when knowledge of results is delayed after the movement. Recording Purkinje cell firing and recording from and inactivating neurons of the parvocellular red nucleus will help to understand their involvement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEURAL MODELING AND IMAGING OF SPEECH Principal Investigator & Institution: Guenther, Frank H.; Associate Professor; Cognitive and Neural Systems; Boston University Charles River Campus 881 Commonwealth Avenue Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-FEB-1996; Project End 31-JAN-2006 Summary: The primary goal of this research project is the continued development, testing, and refinement of a comprehensive computational modeling framework addressing the neural processes underlying speech perception and production. This framework is defined using adaptive neural networks, allowing comparisons with data from imaging studies of brain function. The proposed research includes five modeling studies and nine closely related functional magnetic resonance imaging (fMRI) experiments to test model predictions. These studies constitute five subprojects to flesh out different aspects of the investigators' modeling framework. The first subproject, modeling and imaging studies of neural map formation in the auditory cortical areas,
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will extend their earlier studies into the nature of sound categories in the auditory system (e.g., phonemic categories) and the warping of auditory perceptual space evident from phenomena such as categorical perception and the perceptual magnet effect. The second subproject, modeling and imaging studies of visual influences on speech perception, will extend the investigators' earlier work studying the nature of visual influences on speech perception as evidenced by the McGurk effect, and will address learning processes hypothesized to underlie visual-auditory associations. The third subproject, modeling and imaging studies of central aspects of the DIVA model, will address the neural processes underlying the control of speech articulations, including the involvement of the cerebellum in normal subjects and subjects with cerebellar damage, and the effects of auditory and somatosensory feedback perturbations to activations in different brain areas. The fourth subproject, modeling and imaging studies of movement selection, initiation, and sequencing, will address the involvement of the supplementary motor area, anterior cingulate area, and basal ganglia in speech production. In the fifth subproject, a distributed model of cortical and subcortical interactions in speech, the results of earlier projects will be combined into a comprehensive model of the neural processes underlying speech perception and production. The modeling hypotheses have been specifically designed to be testable with existing or easily attainable fMRI techniques. Several new imaging and data analysis techniques will also be investigated to stay abreast of the most effective methods for testing the hypotheses. When appropriate, these techniques will be utilized to improve the experiments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROPATHOLOGY SCHIZOPHRENIA
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Principal Investigator & Institution: Roberts, Rosalinda C.; Professor; Psychiatry; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Schizophrenia is a devastating illness, with unknown pathophysiology, that affects 1% of the world's population. The experiments in the following revised proposal will focus on the basal ganglia and dopamine (DA) pathology in schizophrenia (SA1) and relate these changes to those occurring in rats treated with antipsychotic drugs (APDs) (SA2). Our preliminary data shows abnormalities in morphology of DAergic neurons in the substantia nigra (SN) and in the number of TH+ striatal synapses in electron microscopic (EM) studies of postmortem tissue from subjects with schizophrenia (SZ), similar structural changes and a decrease in number of TH+ cells in rats treated with APD. SA1 tests the hypothesis that the DA system is perturbed in the basal ganglia of SZ, using tissue from normal controls, SZ treated with typical or atypical APDs or off-drug. SA2 tests the hypothesis that anatomical changes observed in SN and ventral tegmental area (VTA) of SZ are the results, in part, of APDs, and will determine the contributing physiological mechanisms. In both aims, we will determine if the morphological alterations seen will show regional variations that are consistent with the differential effects of typical and atypical APDs on the activity of midbrain DA neurons. In this revision, we have modified the EM analysis of the SN and added 3 parallel experiments in both the human tissue and rats (treated with haloperidol or clozapine or controls). In SA1a the synaptic organization of DA labeled profiles will be analyzed in the human striatum at the EM level. In SA1b & SA2a, the number and size of Nissl stained, and TH+ cells double labeled with the DA transporter (DAT), or a selective marker of DA cells, SK3, will be determined using
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stereological methods in the SN/VTA. In SA1c & SA2b at the EM level, the integrity of subcellular organelles and the synaptic organization to the TH+ neurons (also labeled with DAT or SK3) will be studied. Using in situ hybridization SA1d & SA2e will determine if TH synthesis is affected at the level of transcription. SA1c & SA2d will determine if cytoskeletal proteins are upregulated. SA1f & SA2e will determine if the loss of TH in neurons is due to changes at the translational level by using Western blot analysis. SA2f will study the time course of the anatomical changes observed during APD treatment and relate these changes to the development of depolarization (DP) block. SA2g tests the hypothesis that morphological alterations in SN/VTA neurons will not occur in rats treated with APD if DP block is prevented (with a unilateral striatal lesion). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NEUROPHARMACOLOGY OF DRUGS OF ABUSE--AMPHETAMINE Principal Investigator & Institution: Rebec, George V.; Chancellors' Professor of Psychology And; Psychology; Indiana University Bloomington P.O. Box 1847 Bloomington, in 47402 Timing: Fiscal Year 2002; Project Start 01-AUG-1986; Project End 31-DEC-2003 Summary: (Adapted From The Applicant's Abstract) Amphetamine and related drugs of abuse elicit species-specific motor responses characterized by repetitive or stereotyped patterns. Research on animals, typically rodents, as models of the human response, has implicated the striatum and related basal ganglia circuitry in the motor-activating effects of these drugs. Critical elements of this circuitry include both dopamine- and glutamate-containing fibers that contact neurons in dorsal striatum. During amphetamine-induced motor activation, these neurons establish a pattern of discharge activity mediated, at least in part, by a complex interaction between dopamine and glutamate inputs. Research in this application extends this line of work on behaving animals in two directions. One involves characterization of the neuronal response pattern to amphetamine in substantia nigra pars reticulata, a major target of striatal neurons and an important output nucleus of the basal ganglia. After basic neurobehavioral correlations are established, further studies will examine the extent to which amphetamine-induced changes in reticulata neurons are mediated by the striatum via descending GABA-containing projections. The aim is to determine how amphetamine-induced neuronal response patterns established in striatum are represented in reticulata neurons. A second focus of the proposed research is to examine at the single-neuron level how the major transmitters altered by amphetamine-dopamine and glutamate--interact with each other and with GABA to influence the activity of striatal neurons in an intact, normally functioning animal. Dopamine, glutamate, and GABA will be applied directly by iontophoresis to electrophysiologically isolated single units in awake, unrestrained rats. Attention will center on the mechanisms by which synaptic dopamine modulates glutamate- and GABA- mediated responses. A major component of this work also involved iontophoresis of amphetamine and other indirect dopamine agonists in striatum to determine how local changes in dopamine transmission modulate striatal activity and to reveal the synaptic action of these drugs unaccompanied by concomitant activation of other neuronal pathways. Collectively, these lines of research will provide important new information on the neurochemical systems and processes by which amphetamine alters neuronal function and motor behavior. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEUROPHYSIOLOGY OF BASAL GANGLIA SYSTEM Principal Investigator & Institution: Grace, Anthony A.; Professor; Neuroscience; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-1993; Project End 31-MAR-2003 Summary: (adapted from candidate's abstract): This is a competitive renewal of an RSDA that proposes to use in vivo and in vitro electrophysiological recordings to examine the functional interactions among cortical afferents and the DA system within the NAC of rats. Studies into the etiology of schizophrenia have recently focused on a cortical locus of pathology with emphasis on the prefrontal cortex and the hippocampus. Moreover, owing to the genetic linkage schizophrenia, the impact of developmental disruption has gained prominence in this field. As an extension of our studies demonstrating a gating role for hippocampal input into the NAC, we propose to evaluate the functional interaction NAC afferents and how it may selectively altered by neonatal disruption according to the following specific aims: (1) To characterize the physiology and pharmacology of the responses evoked in NAC neurons in vitro by stimulation of prefrontal cortical, hippocampal, and amygdalar afferents. (2) To examine the pharmacology of DA actions on each of these afferent systems in vitro. (3) to characterize the response properties and types of interaction between pairs of afferents to NAC neurons recorded in vivo. (4) To examine how the DA system affects the afferent-evoked responses and their interactions in vivo, and how these interactions may be altered by psychotropic drugs. This comprehensive characterization of afferent interactions will provide the necessary baseline data for the last specific aim: 5) To compare the effects of developmental disruption in neonates on the interaction between excitatory afferents to the NAC neurons and their regulation by DA in adults. In this way we will gain a better understanding of the nature of these cortical interactions within the NAC, how these systems are modulated by DA, and how they may undergo a compensatory reorganization as a consequence of neonatal damage. In addition to the research plan, an outline for scientific growth over the next five years is presented. This consists of: (1)expanding my participation in basic and clinical research and training; (2) increasing involvement in scientific organizations; (3) taking a leadership role in organizing program project-based research; and (4) expanding the breadth and depth of my laboratory research. This latter goal will be achieved through combination of collaborative ventures using ultrastructural and viral tract tracing techniques, as well as implementing new technologies into my laboratory, including developmental studies and visual patch recordings. Each technique is advanced to address specific research questions rather than simply expanding my technical base. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: NEUROPHYSIOLOGY OF WORKING MEMORY IN BIPOLAR DISORDER Principal Investigator & Institution: Adler, Caleb M.; Psychiatry; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: (provided by applicant): This NIMH Mentored Patient-Oriented Career Development (K23) Award application is to support Dr. Caleb M. Adler's developing expertise in neuroimaging and bipolar disorder. Bipolar disorder is a common psychiatric illness accompanied by severe morbidity and mortality. Traditionally viewed as a cyclic illness with a return to baseline function between affective episodes, evidence suggests that bipolar disorder is associated with significant deficits in specific
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cognitive domains, particularly working memory. Neuroimaging studies in bipolar patients suggest dysfunction of structures associated with the "network" of brain regions involved in working memory. Consistent with these observations, working memory deficits are observed in bipolar patients across the affective spectrum, suggesting that these deficits represent a "core symptom" of bipolar disorder, rising out of the neurophysiology of the illness. The specific research supported by this award will involve studying neuronal activity associated with working memory inpatients with bipolar disorder and healthy volunteers. The candidate will use fMRI to study patterns of activation in bipolar patients and healthy volunteers while they are performing a series of working memory tasks increasing parametrically in difficulty. Both medicated and unmedicated bipolar patients will be enrolled. In addition to increasing understanding of the neurophysiology underlying working memory deficits in bipolar patients, the candidate seeks to improve our understanding of the effects of medication on activation patterns. A better understanding of this "core symptom" may help clarify the underlying neurophysiologic substrates of bipolar disorder, ultimately suggesting future treatment directions. As a follow-up protocol, the candidate will compare working memory-induced activation in bipolar patients during acute mood states with the previously obtained euthymic data. Working memory deficits are exacerbated in depression and mania; these comparisons may clarify changes in the neurophysiology of bipolar disorder during acute affective episodes. During the course of this K23 award, the candidate will obtain additional training in bipolar psychopathology, functional imaging techniques, cognitive testing and statistical analysis, as well as research ethics. The candidate will integrate these skills with previous training and experience in other areas of functional imaging and clinical psychiatry in order to develop expertise in the investigation of the neurophysiology of bipolar disorder. At the conclusion of this award, the candidate will be well positioned to function as an independent investigator extending this work using other cognitive paradigms and to further examine staterelated cognitive deficits in bipolar disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NIGROSTRIATAL DOPAMINE FUNCTION Principal Investigator & Institution: Tepper, James M.; Professor; None; Rutgers the State Univ of Nj Newark Blumenthal Hall, Suite 206 Newark, Nj 07102 Timing: Fiscal Year 2003; Project Start 01-FEB-1997; Project End 31-MAR-2008 Summary: (provided by applicant): The basal ganglia, and especially the dopaminergic components of this system, are well known to play a central role in the role in the etiology and pathophysiology of several neurological and psychiatric disorders including Parkinson's disease and schizophrenia. More recently, however, mesotelencephalic dopaminergic systems have also been viewed as integral to certain types of learning and memory, affective responses and perception, and several types of higher cognitive function. In vivo, dopaminergic neurons fire spontaneously at low rates. This activity exists along a continuum of firing pattern from a regular pacemakerlike pattern on one end, to an irregular or random pattern to a slow bursty pattern on the other end. Dopaminergic neurons in vivo typically respond to behaviorally relevant environmental stimuli with an increase in firing rate in the form of a low frequency burst that usually lasts for a few hundred milliseconds. The timing of the dopaminergic signal is crucial for many of the functions ascribed to the dopaminergic system in signaling stimulus characteristics, reward salience or predictive error. Although it is clear that switches to the different patterns of activity are triggered by afferent activity, the afferents responsible and in particular the mechanisms of the burst or burst initiation
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are not clear. It is the overall goal of this competing renewal to extend observations made in the last Brant cycle by concentrating on GABAergic mechanisms in the afferent control of substantia nigra dopaminergic neurons studied by in vivo and in vitro neurophysiology, light and electron microscopy and in vivo microdialysis. There are 5 specific aims that will test the following hypotheses: (1) GABA-A receptors on dopaminergic neurons re predominantly or exclusively activated by GABAergic inputs in vivo under typical experimental conditions and activation of GABA-B receptors only occurs when the GABA transporter is saturated by excessive or high frequency Input and/or pharmacological blockade, (2) Most postsynaptic GABA-B receptors on substantia nigra dopaminergic neurons are located perisynaptically, (3) Afferent induced alterations in the pattern of activity of DAergic neurons lead to significant changes in extracellular levels of DA in striatum and substantia nigra, (4) Nigral GABAergic interneurons ore a source of afferent input to DAergic neurons, and (5) The difference in sensitivity to GABA-A receptor agonists between DAergic and GABAergic neurons in substantia nigra is due to a differential GABA-A subunit composition and/or a difference in the density of GABA-A receptors. These data should provide answers to several important questions about the afferent control of nigral dopaminergic neurons which are essential for understanding the normal function of the basal ganglia and which may also point the way toward improved pharmacotherapies for disorders involving the dopamine system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: NITRIC OXIDE CONTROL OF CGRP IN TRIGEMINAL NEURONS Principal Investigator & Institution: Durham, Paul L.; Biology; Southwest Missouri State University 901 S National St Springfield, Mo 65802 Timing: Fiscal Year 2002; Project Start 01-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The objective of the proposed research is to understand the mechanisms by which nitric oxide (NO) regulates calcitonin generelated peptide (CGRP) gene expression in trigeminal neurons. Serum levels of CGRP are elevated in alt forms of vascular headaches, including migraine. The neuropeptide CGRP is known to play a critical role in the underlying pathology of migraine due to its ability to regulate cerebral blood flow, mediate neurogenic inflammation, and relay nociceptive information to the CNS. Another agent implicated in migraine pathology is nitric oxide (NO). Glyceryl trinitrate, an exogenous NO donor, triggers migraine attacks, while blockade of NO synthesis aborts acute migraine attacks. The cerebrovascular affect of NO is thought to be mediated by the local release of neuropeptides from trigeminal neurons. In this proposal, I will test the hypothesis that NO directly stimulates CGRP gene expression and determine whether serotonergic anti-migraine drugs can repress the effect of NO. Studies proposed in the first specific aim will determine the effect of NO alone or in combination with other inflammatory mediators on CGRP release from trigeminal neurons and whether the anti-migraine drug sumatriptan can repress this effect. The second aim will focus on identifying the basal and NO-responsive regulatory sites in the CGRP promoter. Primary trigeminal ganglia cultures will be transiently transfected with CGRP-luciferase reporter DNA and reporter activity measured. The effect of sumatriptan on basal and NO-stimulated CGRP promoter activity will be determined. The third aim will elucidate the pathways involved in NO signaling in trigeminal neurons. Initially, specific cyclase and kinase inhibitors and activators will be used to identify the major pathway(s) involved in regulating the synthesis and release of CGRP. Further studies of individual pathways will utilize phosphospecific antibodies and signaling pathway detection kits. The effect
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of sumatriptan on NO-activated pathways will be determined. The overall goal of these studies is to gain insight into basal and NO regulation of CGRP gene expression in trigeminal neurons that may lead to the development of novel therapeutic strategies for migraine and other diseases involving neurogenic inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: OPERATIONAL NETWORKS IN THE AMYGDALA Principal Investigator & Institution: Cassell, Martin D.; Anatomy and Cell Biology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2005 Summary: (provided by applicant): The amygdala is widely recognized as playing a critical role at the interface between emotion and behavior. Much of the interpretation of functional imaging, neuropsychological and pathological studies of the amygdala in anxiety, phobias, depression and drug and alcohol addiction, and the results of a large number of animal experiments, are framed in the context of a linear model of amygdala organization. In this model, inputs from the cortex and thalamus converge on the lateral and basolateral nuclei where learned associations are generated and expressed as autonomic and endocrine changes through the connections of the central, nucleus, the "output" nucleus of the amygdala. However, more and more clinical and experimental findings are becoming difficult to reconcile with this model. The experiments in this proposal are directed at the P.I.'s long term goal of developing a network-based model of amygdala organization with greater interpretative and predictive value. The experiments focus on the central extended amygdala (CEA) not as connecting the rest of the amygdala with autonomic/endocrine areas but as a basal ganglia-like structure involved in re-entrant circuits with the insular cortex, another area increasingly being associated with appetitive drives, emotion and psychiatric disorders. First, combinations of axon tracers will be used to identify the key nodes in re-entrant circuits through the CEA, including a possible "indirect" pathway involving the lateral hypothalamus. Second, immunochemical methods will be used to identify neurochemical compartments in the CEA and determine whether they are organized on the same lines as the nucleus accumbens. Finally, the reconstruction of axons derived from cortical and CEA neurons will be undertaken to examine the likely sequential processing of information by the amygdala network. Preliminary data indicate that the CEA, a socalled "output" structure may receive cortical/thalamic input before the lateral and basolateral nuclei. The experimental results should provide a strong basis for developing a second generation model of amygdala organization offering much greater interpretive value for experimental and clinical studies of psychiatric disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ORGANOCHLORINE EXPOSURE, GENETIC POLYMORPHISM AND PARKINSON'S DISEASE Principal Investigator & Institution: Berkowitz, Gertrud S.; Professor; Mount Sinai School of Medicine of Nyu of New York University New York, Ny 10029 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: (Taken from application) Parkinson?s disease (PD) is a progressive, disabling disorder of the central nervous system characterized by tremors at rest, muscle rigidity, slowness, imbalance and, in later stages, often dementia. It is caused by loss of neurons in the substantial nigra that produce dopamine. Approximately half a million Americans are estimated to be affected by PD. Recent data suggest that environmental
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exposure, possibly in concert with genetically determined vulnerabilities, contribute to causation of PD; particularly in patients with onset of disease above age 50. The study will examine 300 cases of PD whose diagnoses have been confirmed by strict, standardized criteria and 300 controls with "minor" neurologic disorders not involving the basal ganglia. A blood sample will be obtained and a detailed questionnaire will be administered to each case and control. The groups will be half male, half female. All eligible minority patients will be enrolled. Cases and controls will be matched on age, gender, and race. This proposal has two inter-related biomedically based, epidemiologic objectives. We propose to determine: 1) whether serum organochlorine levels and/or a past history of exposure to pesticides are elevated in patients with Parkinson s disease; 2) whether polymorphisms in specific enzymes related to pesticide metabolism are more common in patients with PD; and 3) whether there is evidence for a gene-environment interaction. A more exploratory objective is to evaluate whether diet, particularly intake of antioxidants, may protect against development of PD. To test the hypothesis that organochlorine levels, the most common type of chemical pesticide used between 1940 and 1970, are increased in PD patients, DDT, DDE, Dieldrin, and oxychlordane will be determined and compared between cases and controls. PCB, its congeners and transnonachlor will also be measured since these are organochlorine compounds as well. The gene polymorphism hypotheses will focus specifically on CYP2D6, GSTP1, and PON1. To evaluate the possible protective role of antioxidants, a detailed dietary history will be taken to obtain extensive information on usual antioxidant intake before diagnosis, including Vitamins A, C and E, carotenoids, lycopene, tocopherol and polyphenols (phytoestrogens). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PATHOPHYSIOLOGY OF CHOREA Principal Investigator & Institution: Mink, Jonathan W.; Associate Professor; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 19-JUN-2000; Project End 31-MAY-2005 Summary: Chorea is a movement disorder that results from basal ganglia injury due to a variety of causes in children. Chorea is characterized by sudden, brief, involuntary muscle contractions causing movements that appear to flow from body part to body part in an unpredictable manner. Disorders associated with chorea include CNS infections, post-infectious and other autoimmune diseases, ischemia during cardiopulmonary bypass, 'extrapyramidal' cerebral palsy, a variety of toxic and acute metabolic processes, degenerative conditions, and inborn errors of metabolism. In many cases the cause is unknown. In diseases with well defined neuropathology, chorea has been associated with abnormalities in the striatum (caudate and putamen) and the subthalamic nucleus (STN). However, the fundamental pathophysiology of chorea is not known. This is due in part to the lack of non-primate models and in part to the difficulty of measuring involuntary movements in the primate models that do exist. Current medical treatment options for chorea are few, may have significant side effects, and are often ineffective. The proposed experiments will develop quantitative 3-dimensional kinematic measures of chorea and use them measure spatial and temporal properties of chorea in adults and children with different disorders. Focal pharmacologic manipulation of basal ganglia nuclei will be used in monkeys to produce chorea. The resulting chorea will be measured in the monkeys and compared to human chorea in order to validate the monkey models, especially with respect to childhood chorea. The monkey models will then be used to investigate the fundamental pathophysiology of chorea by recording the activity of individual globus pallidus internal segment neurons
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before and during chorea. Through a combination of neurophysiologic and kinematic techniques to study experimentally produced chorea, the prevailing hypotheses of chorea pathophysiology can be tested rigorously. There is strong potential to identify the fundamental mechanisms of chorea. Development of a non-invasive method to quantify chorea in children and in monkeys will be an important advance toward better characterization of the pathophysiology of involuntary movements and development of more effective medical therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PHARMACOLOGY AND TOXICOLOGY OF METHAMPHETAMINE ABUSE Principal Investigator & Institution: Hanson, Glen R.; Acting Director; Pharmacology and Toxicology; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2003; Project Start 01-AUG-1998; Project End 31-AUG-2006 Summary: (Applicant's Abstract) This is a Senior Scientist Award proposal for Dr. Glen R. Hanson. Dr. Hanson is a tenured professor in the Department of Pharmacology and Toxicology at the University of Utah. He has been active in drug abuse research for over 15 years and has made important contributions to elucidating: (a) the role of dopamine systems in neurotoxicity caused by amphetamine analogs; (b) the role of reactive oxygen species in mediating monoaminergic changes caused by amphetamine analogs; (c) the influence of the stimulants of abuse on neuropeptide systems; (d) the role of dopamine receptor subtypes in the regulation of extrapyrarnidal and limbic neuropeptide systems. Dr. Hanson currently devotes 40-50% of his time to research and student mentoring while 50-60% of his effort is occupied by teaching, departmental and college responsibilities. This Senior Scientist Award will allow Dr. Hanson to increase his research effort to approximately 80%. During the time of support by this award, he will direct research which tests the following principal hypotheses: (a) the generation of dopamine-related reactive oxygen species is a major contributor to the neurochemical deficits occurring in the striatal monoaminergic systems after high doses of methamphetamine (METH); (b) methcathinone, a relatively new designer amphetamine, exerts profound short-and long-term effects on extrapyramidal and limbic monoaminergic systems and has significant neurotoxic potential; (c) METH acutely and selectively alters the nature and function of the dopamine transporter in a reversible manner; (d) low and high doses of METH preferentially influence the indirect (striatalpallidal) and direct (striatal-nigral) efferent pathways to the basal ganglia output nuclei, respectively; (e) changes in neuropeptide systems occur in humans exposed to the potent stimulants of abuse much like that observed in rats after treatment with these same drugs. The increase in research time resulting from a Senior Scientist Award will allow Dr. Hanson to develop expertise in technologies new to his laboratory required to test these hypotheses, such as: (a) free radical analysis; (b) transporter function and ligand assays; (c) in situ hybridization for neuropeptide precursor mRNA. This award will help Dr. Hanson to mentor more effectively inexperienced researchers at the undergraduate, graduate, postdoctoral and young faculty levels as these developing scientists mature and establish themselves in neuroscience research in general, and drug abuse research in particular. In addition, as a mentor Dr. Hanson will be especially supportive of the involvement of underrepresented minorities in drug abuse research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies
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Project Title: PHYSIOLOGY OF ATP RELEASE IN CHRONIC PAIN Principal Investigator & Institution: Matsuka, Yoshizo; None; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant) Chronic inflammatory and neuropathic pain is a problem of considerable clinical relevance. Understanding the mechanisms underlying development and maintenance of chronic pain would be a major step towards rational treatment of such pain conditions. Considerable evidence links chronic pain of neuropathic origin with increased excitability and abnormal signal generation in primary afferent neurons within sensory ganglia. Chemically-mediated cross-excitation between neurons in sensory ganglia has been proposed as one major mechanism by which abnormal discharges can be generated in pathological pain states. However, the identity of the chemical mediator of cross-excitation is unknown. Adenosine triphosphate (ATP) is released within sensory ganglia following neuronal activation and was shown to activate receptors on somata of sensory neurons. The overall goal of this proposal is to directly test the hypothesis that ATP is the chemical mediator of crossexcitation and to determine how release of ATP changes in pathological pain states. The specific aims are to: 1) determine the involvement of released ATP in cross-excitation of neurons within sensory ganglia, 2) determine the changes in basal and stimulus-evoked ATP release after peripheral inflammation, 3) determine the changes in basal and evoked ATP release after induction of sciatic neuropathy, 4) compare ATP release from different types of isolated and labeled DRG neurons. Cross-depolarization evoked by peripheral nerve stimulation will be measured during intracellular recordings from neurons in dorsal root ganglia (DRG). ATP receptors on sensory neurons will be manipulated by application of selective agonists and antagonists to influence evoked cross-depolarization. ATP release will be measured by the luciferin-luciferase assay in DRG perfusates. ATP release from acutely isolated DRG neurons will be measured using detector patches. These studies will be carried out first under normal conditions and then compared to results obtained after induction of a) peripheral inflammation, and b) peripheral neuropathy in rats. The acquired knowledge may lead to the development of novel therapeutics targeting abnormal excitability changes in sensory neurons. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: PRESYNAPTIC NEUROCHEMICAL MARKERS Principal Investigator & Institution: Frey, Kirk A.; Professor of Radiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2003 Summary: Some markers of presynaptic cholinergic nerve terminals such as the enzyme choline acetyltransferase (ChAT) are reduced in the cortex of Alzheimer's disease (AD) patients. Similarly, reductions in dopaminergic indices in the basal ganglia are recognized in Parkinson's disease (PD). These neurochemical changes correlate with the severity of cognitive impairment in AD and with extrapyramidal features in PD. Such marker losses are widely assumed to reflect losses of basal forebrain cholinergic neurons and their terminal projects in AD and of substantial nigra dopaminergic neurons and their striatal terminals in PD. Results obtained in our laboratories indicate that a relatively new class of synaptic markers, vesicular neurotransmitter transporters, are quantitative markers of synaptic terminal losses in neuropathological conditions and are not affected by regulatory changes in response to altered synaptic activity or drug
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treatments. These transporters can now be measured in vitro with ligand binding and immunohistochemistry and in vivo with positron- or single photon emission computer tomography. We recently determined that the vesicular acetylcholine transporter (VAChT) in differentially preserved in AD cortex and hippocampus in comparison to reductions in ChAT activity. This contrasts with results in experimental animals where septo-hippocampal axotomy results in a complete loss of VAChT from the hippocampal formation. Combined, these results suggest that basal forebrain cholinergic neurons in AD are not as depleted as ChAT measures suggest, and that cortical cholinergic innervation may be better structural preserved than previously appreciated. Experiments in the current proposal will characterize further the postmortem neurochemical phenotypes of subcortical cholinergic and dopaminergic projection system in neurodegenerative dementing disorders. We will determine the relationships between cell body and nerve terminal losses in the basal forebrain-to-cerebral cortex cholinergic system and in the midbrain-to-striatum dopaminergic system, employing a combination of histological, ligand binding, immunohistochemical, and mRNA hybridization techniques. We anticipate that distinct, specific and inter-related patterns of cholinergic and dopaminergic pathologies will be found in AD, Lewy body dementias, and PD. These patterns may account for some apparent discrepancies among prior reports of neurochemical pathology in AD and related dementias, and may provide important insights into possible common versus differing pathophysiological mechanisms of dementing diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: PROTEOMICS OF MORPHINE RESPONSES OF THE BASAL GANGLIA Principal Investigator & Institution: Eberwine, James H.; Professor; Pharmacology; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2004; Project Start 15-APR-2004; Project End 31-MAR-2006 Summary: The overall goal of this proposal is to advance a new and powerful paradigm in pulmonary physiology; one we call Image-Functional Modeling (IFM). Conceptually, IFM synthesizes imaging data and mechanical and ventilation function data taken in the same subject with anatomically specific three-dimensional models of the lung. Boston University, as the lead institution will partner with the Massachusetts General Hospital, Brigham and Women's Hospital, Tufts University School of Veterinary Medicine, and the University of Aukland to exploit IFM via the following imaging modalities: Positive Emission Tomography (PET), High Resolution Computer Tomography (HRCT), and Hyperpolarized Helium Magnetic Resonance Imaging (Hyp 3/He MRI). The IFM will be applied to asthma and to respiratory distress syndrome (RDS). Our specific aims are to:. Advance a 3D anatomically specific computational model of the lung that can predict overall and dynamic lung mechanical and ventilation function while permitting the imposition of a heterogeneous insult to explicit anatomic locations. This model will consist of a scaffold of modules across multiple biological scales resulting in an open source simulation resource for the general respiratory structure-function community. Synthesize our computational models with imaging and mechanical functional data taken simultaneously in the same subjects. The imaging data will quantify ventilation distribution and/or airway geometry while the mechanical function data will include standard clinical lung function indices (eg., spirometry) and dynamic lung function. Applications of IFM to asthma and RDS will quantify the likelihood of two hypotheses: a) The primary cause of functional degradation in both ventilation and mechanics during asthma lies within the smafl airways (d
