TECHNOLOGY DEVELOPMENT FOR SAFE AND EFFECTIVE DEEP BRAIN STIMULATION

Release Date:  July 27, 2001

RFA:  RFA-NS-02-004

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

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

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN 
$250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN 
SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

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. During 
the past year, GPi and STN stimulation underwent review at the FDA for 
potential 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 the current guidelines, estimations are that as many 
as 15,000 individuals per year will 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 
success of this therapy in some patients, there is significant room for 
improvement. Complications such as breakage of the electrode lead wires or 
movement of the stimulating electrode occur. Untoward effects arising from 
electrical stimulation of neural tissue other than the target tissue can limit 
stimulation and limit the beneficial effects in some cases. The optimal 
methods for positioning the electrode and the optimal number and size of the 
stimulating electrodes has not been determined. In addition, placement of 
these electrodes carries a small risk of significant complications such as 
intracranial hemorrhage or infection with potential persistent neurological 
disability including hemiplegia or cognitive dysfunction. One other limitation 
to further study of DBS is the lack of suitable stimulation and electrical 
recording systems that would permit study of DBS in appropriate animal models.

Improvement in this treatment modality should be possible through research and 
development to advance techniques for delivering electrical stimulation to 
STN, GPi and other brain structures. This announcement will support research 
to position electrodes in the appropriate target areas, to devise ways to make 
electrode placement more stable, to increase reliability of electrodes and 
electrode lead wires, to develop electrodes and systems capable of recording 
as well as stimulating, to develop electrodes capable of more selective 
stimulation, to develop better stimulators, and to improve the safety of 
implanted systems.

RESEARCH OBJECTIVES

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. The initial 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 by developing advanced methods and hardware for safe and 
effective stimulation of deep brain structures. A companion RFA will be issued 
to request additional research on mechanisms of action of DBS. 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 expand research in the area of technology 
development for DBS. Research is sought in areas of electrode placement, 
electrode stability, stimulator design, lead wire reliability, and other 
factors related to providing safe, reliable DBS therapy. Studies with human 
volunteers are not within the scope of this RFA. Examples of potential 
research topics include:

o The development and validation of better methods of placing electrodes that 
reduce placement time, expense, and morbidity, and that increase accuracy of 
placement.

o The development and validation of better DBS electrodes and lead wires that 
are more reliable, safer to implant and/or provide greater control of the 
stimulation site.

o The development of stimulators that are rechargeable and/or that have a 
wider range of stimulation rates, stimulation currents, pulse widths, pulse 
waveforms, and that permit recording from electrodes as well as stimulation.

o The development of microelectrodes and implantation systems for use in 
animal models of PD and DBS that can simultaneously stimulate and record, do 
microdialysis, or infuse chemicals at multiple sites in multiple brain 
structures involved in the control of movement.

o Studies of the safety of DBS stimulation, including acute effects of 
electrode placement and long-term effects of electrode placement and 
stimulation.

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.

FUNDS AVAILABLE 

NINDS intends to commit approximately $1,500,000 in FY 2002 to fund 2-5 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 plan of NINDS provides 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

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

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 20, 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) 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be 
used in applying for these grants. This version of the 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.

SPECIFIC 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.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  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.  
Additional information about Modular Grants is also available on this site.

The RFA label available in the PHS 398 (rev. 5/2001) application form 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. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

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)

Upon receipt, applications will be reviewed for completeness by the Center for 
Scientific Review and responsiveness by Institute staff.  Incomplete and/or 
non-responsive applications will be returned to the applicant without further 
consideration.

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

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 NINDS National Advisory 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 both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

AWARD CRITERIA

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.

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.

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.

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), 
TECHNOLOGY DEVELOPMENT FOR SAFE AND EFFECTIVE 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 No. 
93.853.  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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