MECHANISMS OF ACTION OF DEEP BRAIN STIMULATION

Release Date:  July 17, 2001

RFA:  RFA-NS-02-003

National Institute of Neurological Disorders and Stroke, NINDS
 (http://www.ninds.nih.gov/)
National Institute of Mental Health, NIMH
 (http://www.nimh.nih.gov/)

Letter of Intent Receipt Date:  September 27, 2001
Application Receipt Date:       November 20, 2001

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  USE THE MODULAR 
BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 (REVISION 5/2001) 
AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.pdf.

PURPOSE

Deep brain stimulation (DBS) in the thalamus for the treatment of tremor was 
approved by the FDA in 1997 following the pioneering work of Benabid and 
colleagues in France. Subsequently it has been found that stimulation in the 
subthalamic nucleus (STN) or globus pallidus (GPi) can relieve multiple 
symptoms of Parkinson's disease (PD).  DBS has been successful in restoring 
significant mobility to a large number of patients with advanced PD. GPi and 
STN stimulation are currently being considered for use to decrease symptoms of 
dyskinesia, tremor, postural instability, and/or bradykinesia in individuals 
with advanced PD. 

Over two thousand patients have been implanted with DBS systems and the number 
is growing rapidly. Using current guidelines estimations are that as many as 
15,000 individuals per year may be candidates for this procedure. This number 
could increase as the population ages and/or if the indications are expanded 
to include PD patients with less advanced symptoms. Despite the exponentially 
increasing use of DBS, the mechanisms of action of this treatment modality 
remain unclear. Based on the difference in time course of different clinical 
effects it seems likely there are a variety of mechanisms operating on 
different time scales. We know little about any of these mechanisms at this 
time. The situation is in some ways similar to an earlier era of 
pharmacological therapy when empiric but effective therapy was used with a 
limited understanding of the mechanisms involved.

There is a need and an opportunity to expand our understanding of how DBS 
produces its beneficial effects. This question needs to be answered at several 
levels ranging from the simplest question of what pathways or cells are being 
inhibited (or stimulated) by DBS to what are the effects of this inhibition 
throughout the motor system over time. Therapeutic effects ranging from the 
acute impact of stimulation on symptoms such as tremor to the potential long-
term effect on disease progression need to be studied. Systems approaches to 
this study may be appropriate as well as cellular and molecular approaches. 
Understanding the mechanism will be critical for the rational design of new 
therapies and for the optimization of current therapies. 

RESEARCH OBJECTIVES

Background

A workshop on DBS was held on the NIH campus on March 3, 1999 to discuss the 
opportunities and needs for further research in DBS.  As a result of the 
recommendations from this workshop the NIH issued an RFA "CONSORTIUM ON DEEP 
BRAIN STIMULATION FOR THE TREATMENT OF PARKINSON'S DISEASE AND OTHER 
NEUROLOGICAL DISORDERS" in September 1999. This RFA called for research on 
animal models, better electrodes and stimulator technology, clinical studies 
and trials, and studies of the mechanism of action of DBS. In response to the 
RFA, we have awarded several grants to investigators and have recruited a core 
group of investigators into a DBS consortium. This follow-up RFA is seeking 
applications that will expand the consortium and strengthen the research 
effort in the area of mechanisms of action of DBS. A companion RFA will be 
issued to request additional research to develop advanced methods of safe and 
effective stimulation of deep brain structures. As the third arm of the 
consortium, investigators interested in clinical trials of DBS are encouraged 
to contact NINDS staff to discuss opportunities to conduct clinical studies 
and trials in this area. 

Research Goals and Topics:
The goal of this announcement is to foster research that will provide a better 
understanding of the sites and/or mechanisms of action of DBS in reducing the 
symptoms and in potentially modifying the course of PD. Examples of potential 
research topics include:

o Studies, including the development of in-vivo and in-vitro models, to 
further refine the understanding of the functional organization of basal 
ganglia and other parts of the motor control network and their role in the 
regulation of behaviors, such as voluntary movement.

o Studies of the stimulatory and/or inhibitory effects of DBS on specific 
pathways, fibers of passage, and cell bodies in STN or Gpi.

o Studies of the acute and long-term effects of DBS on the motor activity 
patterns in areas of the motor system that do not receive direct stimulation.

o Studies of the effect of DBS on gene expression and synaptic plasticity in 
areas of the motor system that do not receive direct stimulation.

o Preclinical studies in a suitable animal model of the possibility that 
intervention with DBS in the early phase of Parkinson's disease modifies the 
progression of the disease.

o Studies in a suitable animal model of the effect of DBS on non-motor 
symptoms of PD. 

o Parametric studies in a suitable model of the effects of stimulation 
parameters or stimulation location on the symptoms of PD.

o The development of improved animal models showing progressive degeneration 
that allow the study of the physiology of brain stimulation in the normal and 
diseased or injured brain and the changes chronic stimulation evokes.

SPECIAL REQUIREMENTS

Consortium and Annual Meeting:  Investigators who participate in this RFA will 
collaborate with other investigators in the previously established consortium 
for DBS. Synthesis of the individual investigator’s research projects into an 
integrated research effort on Deep Brain Stimulation will require 
multidisciplinary collaboration and communication of research results and 
opportunities.  To facilitate such interactions, the NINDS, NIMH and NIA will 
hold a yearly DBS Workshop.  The PI and one other representative from each 
project will attend this meeting in Rockville, Maryland. This meeting will 
also be open to interested members of the research community. The cost of 
traveling to the annual meeting should be built into the proposed budget.

Collaborative Studies: The consortium structure is put in place to facilitate 
collaboration among participating investigators. A mission of the consortium 
is to foster joint collaborative initiatives among members. To this end, a 
Steering Committee composed of the NINDS, NIMH and NIA Program Directors, 
invited consultants, and the Principal Investigators will review and approve 
plans for collaboration. The cost of participating in collaborative studies 
should be estimated at 20% of the basic cost of the grant for years beyond 
year one. Allocation of some or all of these funds will be optional and will 
depend upon approval by the Program Directors at the recommendation of 
Steering Committee based on proposed collaborations.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) R01 award mechanism.  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for an 
application submitted in response to this RFA may not exceed 5 years.  This 
RFA is a one-time solicitation.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary peer review procedures.  The earliest 
anticipated award date is July 1, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE 

NINDS and NIMH intend to commit approximately $2,900,000 in FY 2002 to fund 5 
to 7 new and/or competitive continuation grants in response to this RFA. An 
applicant may request a project period of up to 5 years and a budget for 
direct costs of up to $400,000 per year. Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of each award will 
also vary. Although the financial plans of the ICs provide support for this 
program, awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of meritorious applications. 

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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 concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

William J. Heetderks, M.D., Ph.D.
Repair and Plasticity, NINDS
Neuroscience Center 
6001 Executive Blvd
Room 2207, MSC 9525
Bethesda, MD  20892-9525
Telephone: (301) 496-1447
Fax: (301) 480-1080
Email:  heet@nih.gov

Eugene J. Oliver, Ph.D.
Neurodegeneration, NINDS
Neuroscience Center
6001 Executive Blvd
Room 2203, MSC 9525
Bethesda, MD 20892-9525
Telephone: (301) 496-5680
FAX: (301) 480-1080
E-mail: eo11c@nih.gov

Kevin J. Quinn, Ph.D.
Chief, Behavioral and Integrative Neuroscience Research Branch
National Institute of Mental Health
6001 Executive Blvd
Room 7168, MSC 9637
Bethesda, MD 20892-9637
Telephone: 301-443-1576
E-mail: kquinn@mail.nih.gov

Direct inquiries regarding review issues to:

Lillian M. Pubols, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center Suite # 3208
6001 Executive Blvd.
Bethesda, MD 20892-9529 
Tel.: 301-496-5324/9223
E-mail: LP28E@NIH.GOV

Direct inquiries regarding fiscal matters to:

Brenda Kibler
Grants Management Branch, NINDS
Neuroscience Center
6001 Executive Blvd
Room 3290, MSC 9537
Bethesda, MD 20892-9525
Telephone: (301) 496-9231
EMAIL: kiblerb@ninds.nih.gov

Joy Knipple
Grants Management Branch
Division of Extramural Activities
National Institute of Mental Health
6001 Executive Blvd, Rm 6115, MSC 9605
Bethesda, MD 20892-9605
(301) 443-8811 (V)
(301) 443-6885 (F)
Email: knipplej@nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted.  Although a letter of 
intent is not required, is not binding, and does not enter into the review of 
a subsequent application, the information that it contains allows IC staff to 
estimate the potential review workload and plan the review.

The Letter of Intent is to be sent to:

William J. Heetderks, M.D., Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center
6001 Executive Blvd., Room 2207
Bethesda, MD 20892-9525
Email: Heet@nih.gov

SCHEDULE SUMMARY

Letter of Intent Receipt Date:    September 27, 2001
Application Receipt Date:         November 20, 2001
Peer Review Date:                 March, 2002
Council Review:                   May, 2002
Earliest Anticipated Start Date:  July, 2002

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in 
applying for these grants. This version of PHS 398 is available in an 
interactive, searchable PDF format. Although applicants are strongly 
encouraged to begin using the 5/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using the 
4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, 
the NIH will return applications that are not submitted on the 5/2001 version.  
For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: 
GrantsInfo@nih.gov.

STEP-BY-STEP INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 

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 NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in 
applying for these grants, with the modifications noted below.  Applicants are 
permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled 
application receipt dates until January 9, 2002.  If you are preparing an 
application using the 4/1998 version, please refer to the step-by-step 
instructions for Modular Grants available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

The RFA label available in the PHS 398 (rev. 5/2001) application form 
(http://grants.nih.gov/grants/funding/phs398/labels.pdf) must be affixed to the 
bottom of the face page of the application.  Type the RFA number on the label.  
Failure to use this label could result in delayed processing of the application 
such that it may not reach the review committee in time for review.  In addition, 
the RFA title and number must be typed on line 2 of the face page of the 
application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and three 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)

At the time of submission, two additional copies of the application must be 
sent to:

Lillian M. Pubols, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center Suite # 3208
6001 Executive Blvd.
Bethesda, MD 20892-9529 (For Fed Ex or other courier use Rockville, MD 20852)

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA 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 substantial 
revisions of applications already reviewed, but such applications must include 
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NINDS.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NINDS in accordance with the review criteria stated below.  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 the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the either the NINDS National Advisory Council or the National 
Advisory Mental Health Council.

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 the application 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 assigning the overall score, 
weighting them as appropriate for each application.  Note that 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.

(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:  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?

(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 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

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

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 sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 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/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
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.  Program staff may also provide additional relevant 
information concerning the policy.

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.

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 RFA (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.

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.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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 Request for Applications (RFA), 
MECHANISMS OF ACTION OF DEEP BRAIN STIMULATION, 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 Nos. 
93.853 (NINDS) 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 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 
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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