RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENT DISORDER Release Date: May 2, 2001 PA NUMBER: PA-01-086 (This PA has been reissued, see PA-05-032) National Institute of Neurological Disorders and Stroke National Heart, Lung, and Blood Institute National Institute on Aging National Institute of Mental Health THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), the National Heart, Lung, and Blood Institute, and the National Institute of Mental Health (NIMH) encourage investigator-initiated research grant applications to study restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). The etiologies of these disorders are unknown, although there is evidence that central dopamine mechanisms are involved. Research should be aimed at an understanding of the pathogenesis of RLS and PLMD that will lead to new forms of treatment. The intent of this announcement is to intensify investigator-initiated research, to attract new investigators to the field, and to enhance interdisciplinary approaches to research in these areas. RESEARCH OBJECTIVES Background Restless legs syndrome is a common neurological disorder characterized by unpleasant sensations of the legs and an urge to move them for relief. Because symptoms are intensified by inactivity and lying down, RLS patients often have difficulty falling asleep and staying asleep. Left untreated, RLS causes exhaustion and fatigue, which can affect occupational performance, social activities, and family life. Most prevalence estimates are around 2-5% of the population, although many more may be affected because the disorder is often not diagnosed. Severe RLS is more common in the elderly, affecting an estimated 10-11%, although symptoms may develop at any age. The etiology of RLS probably involves central dopamine mechanisms, and both dopaminergic agents and dopamine agonists have been used to treat symptoms. RLS is also associated with iron deficiency, indicated by low ferritin levels. These levels appear to follow a circadian cycle, and are at their lowest at night when RLS symptoms are the worst. The frequency of RLS during late stage pregnancy is increased, which may be related to iron deficiency. Many people with RLS report a family history of the disorder, but the exact mode of inheritance is unknown. It has been estimated that about 80% of RLS patients also have periodic limb movement disorder (PLMD), or nocturnal myoclonus, which is characterized by repetitive stereotyped movements of the limbs, primarily the legs, during sleep. These movements typically occur every 20 to 40 seconds, and may be associated with repeated arousal, and severely fragmented sleep. In a study of patients with insomnia, PLMD or RLS was diagnosed in 33% of patients older than 60 years as compared to 18% of those 40 to 60 years and 7% of those 20 to 40 years of age. Like RLS, the etiology of PLMD may involve a central dopamine mechanism, because it also responds to dopaminergic drugs. However, treatment with dopaminergic agonists can augment the symptoms, possibly by a continuation of the underlying progressive inhibition of dopaminergic neuronal activity. Current investigations indicate that both RLS and PLMD occur in a substantial number of patients suffering from Parkinson’s disease and narcolepsy, two other disorders thought to involve central dopamine mechanism. Greater understanding of the role of dopamine systems in the etiology of these all of these disorders may provide a key to new treatment and prevention strategies. In order to develop a research agenda, the NIH sponsored a Dopamine Connection Workshop. The workshop resulted in the identification of research needs from a broad spectrum of the scientific community expert in dopamine systems, sleep, genetics, and movement disorders. Scope and Objectives The major focus of this announcement is to enhance our understanding of the pathogenesis of restless legs syndrome and periodic limb movement disorder in order to develop more effective treatment strategies. Studies in both humans and animal models are encouraged. Investigators with diverse scientific interests are invited to apply their expertise in basic and applied research in areas including, but not limited to, the following: o family studies to distinguish genetic and non-genetic forms and to map, identify, and characterize genes involved in the etiology of RLS/PLMD o epidemiological studies to determine incidence and prevalence of RLS and PLMD in the population as a function of sex, age, and/or ethnic group o development of genetic models of RLS/PLMD in both small and large animals o studies in animals exposed to precipitants of RLS/PLMD, e.g., iron depletion or uremia o studies to determine how dopamine pathways are altered in RLS/PLMD o studies on the role of iron in the pathogenesis of RLS/PLMD o studies of the anatomy, physiology, and regulation of muscle tone in RLS/PLMD o studies of the relationship among circadian rhythms, sleep, dopamine level, and RLS/PLMD o studies of other oscillatory phenomena, e.g., the 20-second oscillation of dopamine-sensitive neurons, and possible relationship to PLMD and sensory symptoms in RLS o studies of the relationship between opiate sensitivity and sensory symptoms o identification of biological markers that could be used in diagnostic or treatment studies o studies of the effect of movement on sensory symptoms in RLS o studies of the relationship between RLS and attention deficit disorder with hyperactivity o studies to compare periodic limb movements in RLS and other conditions, e.g., narcolepsy, uremia, peripheral neuropathy, or Parkinson’s disease o dosage studies of the treatments currently used for RLS/PLMD o studies of previously unexplored treatments for RLS/PLMD MECHANISM OF SUPPORT The mechanism of support will be the National Institutes of Health (NIH) research project grant (R01). Applications will be assigned by the Center for Scientific Review to participating Institutes according to the regular guidelines for referral. All awards will be administered under PHS grants policy as stated in the NIH Grants Policy Statement (March 1, 2001). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. For scientific issues, contact: Paul L. Nichols, Ph.D. National Institute of Neurological Disorders and Stroke Neuroscience Center, Rm. 2108 6001 Executive Blvd. Bethesda, MD 20892 Phone: (301) 496-9964 Fax: (301) 402-2060 E-mail: Carl E. Hunt, M.D. National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 10138 6701 Rockledge Drive Bethesda, MD 20892 Phone: (301) 443-0199 Fax: (301) 480-3557 E-mail: Andrew A. Monjan, Ph.D., M.P.H. National Institute on Aging Gateway Building, Suite C3C07 7201 Wisconsin Ave. Bethesda, MD 20892 Phone: (301) 496-9350 Fax: (301) 496-1494 E-mail: Israel I. Lederhendler, Ph.D. National Institute of Mental Health Neuroscience Center, Rm. 7169 6001 Executive Blvd. Bethesda, MD 20892 Phone: (301) 443-1576 Fax: (301) 443-4822 E-mail: Direct questions regarding fiscal matters to: Denise Chatman Grants Management Branch National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 3290 6001 Executive Blvd. Bethesda, MD 20892 Phone: (301) 496-9231 Fax: (301) 402-0129 E-mail: Robert Vinson Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, Maryland 20892-7926 Telephone: 301 435-0171 FAX: 301 480-3310 E-mail: Linda Whipp Grants Management Officer National Institute on Aging Gateway Building, Suite 2C218 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 E-mail: Diana S. Trunnell Grants Management Branch National Institute of Mental Health Neuroscience Center, Room 6115 6001 Executive Blvd. Bethesda, MD 20892 Phone: (301) 443-2805 Fax: (301) 443-6885 E-mail: APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98)is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, Email: The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 is to be used in applying for these grants, with the modifications noted below. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS - Modular grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE - Items 7a and 7b should be completed, indicating direct costs (in $25,000 increments up to a maximum of $250,000) and total costs (modular total direct plus facilities and administrative [F&A] costs) for the initial budget period. Items 8a and 8b should be completed indicating the direct and total costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see for sample pages). At the top of the page, enter the total direct costs requested for each year. This is not a Form page. Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and their role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: Complete the educational block at the top of the form page. List position(s) and any honors. Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. List selected peer-reviewed publications with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete and responsive to the PA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written review, comments on the following aspects of the application will be made in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score. (1) Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach. Is the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to that institute/center (IC). The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, published in the NIH Guide for Grants and Contracts on August 2, 2000 ( The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: Investigators also may obtain copies of these policies from the program staff listed under Inquiries. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010, a PHS-led national activity for setting priority areas. This PA Restless Legs Syndrome and Periodic Limb Movement Disorder, is related to the priority area of hypothesis-driven studies of nervous system disease. Potential applicants may obtain a copy of Healthy People 2010 at AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.853 (NINDS), 93.866 (NIA), 92.233 (NHLBI), and 93.242 (NIMH). Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routing education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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