PATHOGENESIS AND TREATMENT OF DYSKINESIAS IN PARKINSON'S DISEASE

RELEASE DATE:  July 18, 2002

PA NUMBER: PAS–02-129

EXPIRATION DATE:  November 2, 2005, unless reissued.

National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)

THIS PA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS PA

With this Program Announcement, the National Institute of Neurological 
Disorders and Stroke (NINDS) invites research grant applications (R01) that 
address the development and treatment of dopamine-induced dyskinesias, a 
major complication of current pharmacotherapy of Parkinson's disease.  The 
purpose of this initiative is to 1) support the study of the pathophysiologic 
basis of dopamine-induced dyskinesias; and 2) support the study of non-
dopaminergic pharmacologic agents for the treatment of dopamine-induced 
dyskinesias.

RESEARCH OBJECTIVES

Dyskinesias constitute an important complication of the treatment of 
Parkinson's disease (PD).  Soon after the recognition that loss of 
dopaminergic neurons in the substantia nigra is the primary pathophysiologic 
finding in PD the strategy of dopamine replacement by administration of its 
precursor, levodopa, quickly became the standard therapy for PD.  However, 
more than half of all patients treated with levodopa or other dopaminergic 
agonists will subsequently develop dyskinesias after approximately five 
years.  In many cases these treatment-induced complications limit the amount 
of drug that can be administered and, as a further result, the amount of 
symptomatic relief that can be obtained.

The clinical presentation of dyskinesias may vary significantly.  These 
abnormal, involuntary movements may be choreic or dystonic; they are 
heterogeneous with respect to affected body part and may be associated with 
other motor symptoms; and they may be associated with high, low or 
intermediate blood levels of dopamine.  When severe or painful, they limit 
therapy but when mild they can be well tolerated by patients.  However even 
when mild, it is widely held that the appearance of dyskinesias foreshadows 
the development of other, more disabling motor complications.  Therefore, 
even mild dyskinesias may lead the treating physician to reduce dopaminergic 
therapy – at the price of increased rigidity for the patient. 

The pathogenesis of dyskinesias is poorly understood.  In several areas the 
available data are incomplete or in conflict.  For instance, dyskinesias may 
be induced by either dopaminergic agonists or antagonists (levodopa induced 
or tardive dyskinesias, respectively) and can reflect low or high 
concentrations of dopamine (dystonia and chorea, respectively).  While it is 
well established that dopamine-induced dyskinesias typically develop after 
the sustained pulsatile administration of a dopamine agonist to a subject 
(human or primate) with a significant nigral dopaminergic deficit such as in 
PD, it is clear that dyskinesias can also develop in subjects with intact 
nigral dopaminergic systems.

Our understanding of the physiologic basis of dopamine-induced dyskinesias is 
similarly incomplete.  According to the current model of the basal ganglia, 
dopamine-induced dyskinesias should be associated with a particular pattern 
of altered neuronal firing in the globus pallidus (internal and external 
segments) and the subthalamic nucleus; however several indirect measures of 
neuronal activity indicate the opposite pattern.  Similarly, lesions in the 
globus pallidus affect dyskinesias in the opposite pattern than would be 
predicted by the standard model.  Finally, much remains to be learned about 
the physiologic substrate (the specific neurons and their firing patterns) 
underlying the induction and resolution of dyskinesias.

While PD is conventionally considered a disorder of nigral dopaminergic 
neurons, the integrated unit of cerebral cortex, basal ganglia and thalamus 
that is compromised includes many neurotransmitters and neuromodulators.  
These include glutamate, acetylcholine, adenosine, serotonin, opioids, 
cannabinoids and their cognate receptors and subtypes.  Many of these are 
specifically associated with pathways that may be up or down regulated in PD 
and thereby present the opportunity for non-dopaminergic approaches to the 
therapy of PD and its complications.

RESEARCH SCOPE

Dyskinesias constitute an important complication of PD in three ways.  First, 
they are intrinsically disabling; second, they limit the symptomatic 
management of the majority of advanced patients; and third, they highlight 
the limitations of our current understanding of basal ganglia structure and 
function.  There is a particular need to investigate the pathogenesis, 
pathophysiology and treatment of dyskinesias in PD patients and primate 
models.  Accordingly, applications are solicited to study the following 
aspects of dyskinesias in the context of PD:

Pathogenesis and pathophysiology
o Physiological and functional imaging studies in MPTP-treated primates 
followed by molecular neuroanatomy to establish the altered circuitry of 
dyskinesia.
o Intraoperative recordings from humans during surgery to alleviate 
dyskinesias.

Treatment
o Pre-clinical studies of non-dopaminergic agents in dyskinetic primates;
o Development and validation of clinical tools such as a dyskinesia rating 
scale or a predictor of motor complications*;
o Pilot studies of non-dopaminergic agents in dyskinetic Parkinsonian 
patients*.

*It is expected that such studies will also conform to the NINDS Pilot 
clinical trial grant program announcement (PAR–01–119, 
http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html) and such 
studies should be submitted under the auspices of
PAR–01-119.  Potential applicants should be aware that this PAR includes 
additional review criteria and accordingly, are strongly encouraged to 
contact NINDS program staff for guidance.

In summary, a systematic review of the literature indicates that a set of 
focused studies on dyskinesias in PD should be undertaken.  There is a need 
to investigate the pathogenesis, pathophysiology and treatment of dyskinesias 
in PD patients and primate models.  The research plan must be soundly 
developed in the context of the current knowledge/research base, with well-
defined and clear objectives.  Applicants should elaborate on innovative 
aspects of the proposed research and special attributes of the resources and 
environment.

MECHANISM OF SUPPORT 

This PA will use the NIH R01 award mechanism.  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 
http://grants.nih.gov/grants/funding/modular/modular.htm).  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.

At this time, it is not known if this PA will be reissued. Any future 
unsolicited competing continuation applications based on this project will 
compete with all NIH investigator-initiated applications and be reviewed 
according to the customary peer review procedures. 

FUNDS AVAILABLE 

The NINDS intends to commit approximately $2,400,000 to fund up to 6 new 
competitive grants in response to this PA over the course of the next three 
years.  Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration of 
each award will also vary.  Awards pursuant to this PA are contingent upon 
the availability of funds and the receipt of a sufficient number of 
meritorious applications.

ELIGIBLE INSTITUTIONS 

You may submit application 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

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

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.

SPECIAL REQUIREMENTS

As discussed above (RESEARCH SCOPE), some clinical studies responsive to this 
PA will be expected to be submitted under the auspices of the NINDS Pilot 
clinical trial grant program announcement (PAR–01–119, 
http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html).  Since such 
applications must conform to the intent of both program announcements, 
including the additional review criteria of PAR-01-119, potential applicants 
are strongly encouraged to contact NINDS program staff for guidance.

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Paul Sheehy, Ph.D.
Program Director
Neurodegeneration Cluster
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Rm 2214
6001 Executive Blvd MSC 9525
Bethesda, MD  20892-9525
Phone: 301-496-5680
FAX: 301-480-1080
Email: sheehyp@ninds.nih.gov

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

Chris Ann Davis
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Suite 3290
6001 Executive Blvd MSC 9537
Bethesda, MD  20892-9537
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email: davisc@ninds.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

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

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting 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 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:  
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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

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)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  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 
critique.

PEER REVIEW PROCESS

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 
(http://www.csr.nih.gov/refrev.htm) 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

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 comments, reviewers will be asked to discuss the following 
aspects of your 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 your application's overall score, weighting them as appropriate 
for each application.  Your 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, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 
tactics?

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

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  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.

INCLUSION:  The adequacy of 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.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

DATA SHARING:  The adequacy of the proposed plan to share data.

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

OTHER REVIEW CRITERIA:  As discussed above (RESEARCH SCOPE), some clinical 
studies responsive to this PA will be expected to be submitted under the 
auspices of the NINDS Pilot clinical trial grant program announcement 
(PAR–01–119, http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html).  
Since such applications must conform to the intent of both program announcements, 
including the additional review criteria of PAR-01-119, potential applicants 
are strongly encouraged to contact NINDS program staff for guidance.

AWARD CRITERIA

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

REQUIRED FEDERAL CITATIONS 

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components 
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 Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
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 AMENDMENT "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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_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 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
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 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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.

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 PA 
is related to one or more of the priority areas. 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, and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  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 described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92.

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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.