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: pn13w@nih.gov 

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: ch314w@nih.gov  

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: am39m@nih.gov

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: il1n@nih.gov

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: dc55g@nih.gov

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: vinsonr@nhlbi.nih.gov

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: whippl@gw.nia.nih.gov

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: dt21a@nih.gov

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) 435-0714, Email: GrantsInfo@nih.gov.

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 http://grants.nih.gov/grants/funding/modular/modular.htm 
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: http://grants.nih.gov/grants/funding/modular/modular.htm.

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 
(http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm) 
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: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 
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 
http://www.health.gov/healthypeople/.

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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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