RELEASE DATE:  June 2, 2003

PA NUMBER:  PAS-03-131

EXPIRATION DATE: September 30, 2006

National Institute of Neurological Disorders and Stroke (NINDS)
National Heart, Lung, and Blood Institute (NHLBI)

93.838, 93.839


o Purpose of the PA
o Research Objectives
o Mechanisms of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


This is a program announcement (PA) with set-aside funds.  The PA is 
designed to stimulate and support research on sleep disorders in 
Parkinson's disease (PD) and Parkinson's related neurological conditions 
(PRNC).  Support will be for research on PD and PRNC patients as well as 
patients in appropriate comparison groups and/or healthy control subjects.  
Responsive applications could deal with the following areas: natural 
history of symptoms studies, mechanistic studies of the sleep disturbances 
in PD and PRNC, associated sleep disorders such as Restless Legs Syndrome 
(RLS) and sleep-disordered breathing (SDB), and studies of the sleep-
related effects of pharmacotherapies for PD and PRNC.  The timing and scope 
of this PA are predicated on recent research and clinical findings 
indicating promising new directions for the diagnosis and care of patients 
with PD and PRNC. 


Sleep disturbances affect the overwhelming majority of PD patients during the 
course of their illness.  This has significant adverse effects upon quality 
of life and, in some cases, safety on the road and in the workplace.  
Medications prescribed for PD may also affect sleep and wakefulness.  Drugs 
that act on dopamine systems can cause or exacerbate underlying daytime 
sleepiness, and paradoxically, can improve or worsen the quality of nighttime 
sleep.  These problems also extend into the larger population of patients 
with neurodegenerative disorders that exhibit parkinsonian features 
collectively referred to in this PA as Parkinson's related neurological 
conditions (PRNC) and include but are not limited to: Diffuse-Lewy body (DLB) 
disease, multiple systems atrophy (MSA), and RLS.  The wide spectrum and 
ubiquity of disordered sleep and decrements in daytime arousal in PD and PRNC 
patients has prompted re-examination of their 24-hour patterns of wake/sleep.  
Key findings in patients with these conditions are: disrupted nocturnal 
sleep, greater prevalence of periodic leg movements (PLM) and obstructive and 
central sleep apnea relative to controls, sleepiness irrespective of their 
drug therapy, and REM sleep behavior disorder (RBD) as an early 
manifestation.  In RBD, the normal muscle paralysis that occurs during REM 
sleep is disrupted so that patients retain muscle tone allowing them to "act 
out" emotionally laden and often violent dreams.  RBD, therefore, not only 
disturbs the sleep of the bed partner, but also can cause injury to patients 
and others nearby.

The natural history of sleep disturbances in PD and PRNC remains unknown, as 
well as the relationship of sleep disturbances to frequent comorbid 
conditions such as depression and dementia.  Clinical experience and 
increasing evidence from animal studies and animal-models of these disorders 
consistently indicate that altered function of dopamine neurons may account 
for not only the daytime motor symptoms of PD, but also co-morbid 
disturbances in maintenance of a normal sleep-wake cycle.  This PA is 
intended to encourage and support research on PD patients and appropriate 
comparison groups, possibly including healthy control subjects.  Key 
objectives of this PA include: (1) a better understanding of the 
pathophysiological basis of sleep disturbances in treatment-naïve or drug-
free PD and PRNC patients, (2) the extent and characteristics of effects on 
sleep and wakefulness produced by available pharmacotherapies for PD and 
PRNC, and (3) identification of interventions to reduce the burden of sleep-
related symptoms on PD and PRNC patients.  Resulting information will improve 
recognition, diagnosis and treatment of these disorders.  Of particular 
relevance will be studies of mechanisms by which dopamine affects arousal and 
physiological measures of sleep, investigations of natural history of 
disturbed sleep in PD, interactions of medical and surgical treatment of PD 
to disturbed sleep, and neuroimaging or neuropathological characterization of 
patients with well documented PD-related sleep disturbances.  Studies of the 
relationship between sleep disturbances and commonly prescribed medications 
that interact either directly or indirectly with dopaminergic systems will 
also be encouraged.  New research has described a previously unknown 
mesothalamic dopamine system in which the thalamus receives dopaminergic 
inputs from the same cells as those that degenerate in Parkinson's disease.  
Another study has found dopamine neurons in the dorsal raphe, a brainstem 
area rich in serotonin and considered important for the regulation of sleep.  
These findings suggest heretofore unrecognized mechanisms that may be 
relevant to sleep disorders in PD.  Supportable clinical studies will include 
patients with other disorders associated with defects in dopaminergic 
transmission (e.g., DLB, MSA, PLM, and RLS.  It is important to better 
understand the mechanisms by which dopaminergic drugs used outside the realm 
of PD so profoundly affect sleep and motor function.  Such drugs include, but 
are not limited to, amphetamines and phenothiazines.  Since the motor and 
sleep mechanisms affected by PD seem to interact with other transmitter 
systems, such as GABA, norepinephrine, serotonin, acetylcholine, histamine, 
etc., this PA is likely to reveal new understanding of the defects underlying 
PD as well as new therapeutic approaches.

This PA is NOT intended to support clinical trials whose primary aim is to 
evaluate treatment efficacy for the motor symptoms of PD or PRNC.  Examples 
of research that would be considered relevant to this announcement include, 
but are not limited to, the following:

o Studies on the natural history of sleep and wakefulness symptoms in PD and 

o Studies to elucidate mechanisms by which these conditions affect sleep and 

o Studies on the inter-relationship between disturbed sleep and impaired 
wakefulness.  For example, to what extent, in these patient groups, do sleep 
disturbances cause impaired waking function?  To what extent are disturbed 
sleep and impaired wakefulness joint manifestations of the same CNS defect?

o Studies to define possible sub-populations of PD and PRNC appropriate for 
adjuvant pharmacotherapy or modified primary pharmacotherapy, aimed at 
reducing problems with sleep and/or wakefulness.

o Studies to define the extent to which SDB or other sleep disorders 
contribute to impaired wakefulness in PD and PRNC, including studies of upper 
airway motorneuron function.

o Studies to elucidate abnormalities in the neurobiology of hypocretin and 
leptin associated with PD or PRNC and leading to altered chemosensitivity or 
increased upper airway resistance during sleep.

o Preliminary/pilot studies to elucidate mechanisms by which 
pharmacotherapies for these conditions affect sleep and wakefulness.

o Preliminary/pilot studies to identify promising interventions to improve 
the sleep and wakefulness of PD and PRNC patients.

o Preliminary/pilot studies to optimize the intervention strategy (e.g., 
dose, duration, frequency of dosing).  For example, studies designed to 
investigate dose-concentration, dose-response, or concentration-response 
relationships may contribute to optimal dosage selection to minimize adverse 
effects on sleep and wakefulness. 

o Preliminary/pilot studies to assess the appropriate delivery system or 
parameter settings of an electronic device or surgical technique.

o Preliminary/pilot studies to assess the safety and tolerability at various 
doses or concentrations of a specific intervention.

o Preliminary/pilot studies designed to explore pharmacokinetic and 
pharmacodynamic relationships. 

Prospective applicants should be aware that, in some cases, especially in 
connection with protocol and experimental design, there may be convergent 
objectives between the present PA and the PA entitled, "PILOT STUDIES FOR 
encouraged that prospective applicants, who are considering a response to the 
present PA that entails pharmacotherpeutic intervention, discuss the proposal 
with the Clinical Trials Group at NINDS prior to the submission of the 
application (contact below). 

Dr. Scott Janis 
Clinical Trials Group
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2210
6001 Executive Blvd
Bethesda, MD  20892
301-496-9135 (phone)


This PA will use the NIH research project grant (R01) and the program project 
grant (P01) award mechanisms.  As an applicant, you will be solely 
responsible for planning, directing, and executing the proposed project.  

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at


NINDS has set aside $1,500,000 in total costs to fund applications that do 
not score within the NINDS payline (see NINDS Funding Strategy  The amount and 
timing of awards paid from set aside funds will depend on the overall 
scientific merit of the applications and the availability of funds throughout 
the duration of this solicitation (3 years).  NHLBI anticipates funding 1-3 
applications with sufficient merit at levels of support similar to NINDS.  
Assignment will be based on customary NIH referral guidelines.  Although the 
National Institute on Aging (NIA) is not a co-sponsor of this PA, it is 
interested in the support of research on the disorders of sleep that afflict 
the older population.  As such, the NIA would be interested in meritorious 
applications submitted in response to this announcement that are relevant to 
its mission and competitive within its funding plan. 


You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
o Faith-based or community-based organizations 


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs. 


We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Merrill M. Mitler, Ph.D.
Program Director
Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2116
6001 Executive Blvd
Bethesda, MD  20892
301-496-9964 (phone)
301-402-2060 (fax)

Carl E. Hunt, M.D.
Director, National Center on Sleep Disorders Research
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10038
Bethesda, MD    20892-7920
301-435-0199  (phone)
301-480-3451  (fax)

o Direct your questions about financial or grants management matters to:

Karen D. Shields
National Institute of Neurological Disorders & Stroke
Senior Grants Management Specialist
6001 Executive Blvd, Suite 3290
Bethesda, Maryland 20892 (Regular Mail)
Rockville, Maryland 20852 (Courier Service)
(301)496-7393 Direct Line
(301)496-9231 Main Line
(301)402-0219 Fax

Robert Pike
National Heart, Lung, and Blood Institute
Section Chief, Grants Operations Branch
6701 Rockledge Drive MSC 7926
Bethesda, Maryland 20852 
(Courier Service   20817)
301-480-3310 Fax


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at  Application 
deadlines are also indicated in the PHS 398 application kit.

up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step 
guidance for preparing modular grants. Additional information on modular 
grants is available at

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application. 

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study;

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application. 

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types.  Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at  

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

CONDITIONS, and the number of this announcement (PAS-03-131) must be typed on 
line 2 of the face page of the application form and the YES box must be 

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed. This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board  


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 comments, reviewers will be asked to discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these criteria 
in assigning the application's overall score, weighting them as appropriate 
for each application.  The application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, an investigator may propose to 
carry out important work that by its nature is not innovative but is 
essential to move a field forward.

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?

APPROACH: Are 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?

INNOVATION: Does the project employ novel concepts, approaches or methods?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

subjects and protections from research risk relating to their participation 
in the proposed research will be assessed.  (See criteria included in the 
section on Federal Citations, below).
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated.  (See Inclusion Criteria in the sections on 
Federal Citations, below).

be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed. 


BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available funds 
with all other recommended applications. The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 

involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 (
02-001.html); a complete copy of the updated Guidelines are available at
2001.htm.  The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in compliance with 
the new OMB standards; clarification of language governing NIH-defined 
Phase III clinical trials consistent with the new PHS Form 398; and updated
roles and responsibilities of NIH staff and the extramural community.  The 
policy continues to require for all NIH-defined Phase III clinical trials that: 
a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

The NIH maintains a policy 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 is available at 

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment. NIH has provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application.  In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at

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.  Furthermore, 
we caution reviewers 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 RFA is 
related to one or more of the priority areas. 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 at and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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 routine 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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