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 301/710-0267, 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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