Release Date:  September 27, 1999

RFA: NS-99-006

National Institute of Neurological Disorders and Stroke
National Institute on Aging

Letter of Intent Receipt Date:     November 15, 1999
Application Receipt Date:          February 16, 2000 



In response to the resurgence of interest in the application of neurosurgical
approaches to the treatment of movement disorders and especially Parkinson's
disease, the National Institute of Neurological Disorders and Stroke (NINDS)
and the National Institute on Aging (NIA) invite qualified investigators to
submit grant applications for a broad range of studies aimed at improving the
use of deep brain stimulation as a therapy.  The purpose of this Request for 
Applications (RFA) is to encourage additional basic and clinical studies into
the mechanisms of a potentially reversible, adjustable and long term
electrical treatment of neurological disorders.  It is expected that this
research will produce a greater understanding of the circuitry involved in 
movement and related disorders, the development of improved electrodes for use
in deep brain stimulation, and improved treatment.

This RFA will create a consortium of research programs in deep brain
stimulation that will serve as a focal point for collaboration and expansion
of the field. Investigators in the consortium will conduct research within
their areas of expertise and will also collaborate with other consortium 
members to develop interdisciplinary projects that pool results and expertise
available in the individual projects. 


The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, "Deep Brain Stimulation for
the Treatment of Parkinson's Disease and other Neurological Disorders" is
related to the priority area of chronic disabling conditions.  Potential 
applicants may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
17-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202/512-1800).


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 


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

The mechanism of support for this initiative is the regular research grant
(R01).  Responsibility for planning, direction and execution of the proposed
research will rest solely with the applicant. Because the nature and scope of
the research proposed in response to this RFA may vary, it is anticipated that
the size of the award may also vary. This RFA is a one-time solicitation. 
Future applications will compete with all investigator-initiated applications
and be reviewed according to the customary peer-review procedures. 

Investigators seeking to carry out pilot studies of clinical research in
preparation for a clinical trial are encouraged to make use of the "NINDS
Pilot Clinical Trial Grant (R01) For Neurologic Disease" as described in
Program Announcement PAR-97-103, August 29, 1997.


The NINDS and NIA will allocate up to 5 million dollars in total costs to
support applications responding to this RFA in FY 2000. Applicants may request
up to five years of support.  In all cases, facilities and administrative
(indirect) costs will be awarded based on the negotiated rates.  The award of
grants pursuant to this RFA is contingent upon the receipt of a sufficient
number of high quality applications and the availability of funds for this
purpose.  Policies that govern research grant programs of the National
Institutes of Health are applicable to all procedures in the receipt, review
and support of this RFA.


The overall purpose of this initiative is to continue to support and stimulate
the progress on deep brain stimulation as a treatment for Parkinson's disease
and related neurodegenerative disorders. Chronic electrical stimulation
through electrodes implanted deep in the brain can relieve the symptoms of
Parkinson's disease. Based on results from only about 30 patients, the FDA
recently approved deep brain stimulation (DBS) within the thalamus for relief
of tremor of Parkinson's disease and also for non-Parkinsonian "essential
tremor."  Tremor is often not the most troublesome symptom of Parkinson's
disease. Now, evidence, mostly from Europe, suggests that DBS can relieve
other, more debilitating symptoms of Parkinson's disease such as bradykinesia
and rigidity. Not only does the benefit appear to be long lasting, but also
there is tantalizing evidence that chronic stimulation may slow progression of
the disease. Side effects of chronic stimulation seem to be less problematic
than drugs, and stimulation therapy is less destructive than surgical ablation
therapies, and thus potentially reversible if more complete treatments become

The promise of DBS emphasizes in a dramatic way the importance of electrical
activity in reorganizing neural circuits and brain function. DBS may also
alter the response of cells to intrinsic signaling molecules and, perhaps, to
drugs. How activity modifies the nervous system is among the most active and
important areas in neuroscience.

The National Institute of Neurological Disorders and Stroke convened a
Workshop on Deep Brain Stimulation for Parkinson's Disease on March 3, 1999 in
Bethesda, MD to evaluate the current information and identify the need for
future research.  The Workshop concluded that DBS is one of the most dramatic
advances in decades for treatment of neurological disorders.  It provides a
powerful effect with obvious benefit in the treatment of Parkinson's disease,
and with potential benefit in the treatment of other neurological disorders.   

Accordingly, the following suggestions are made for further work:

O Studies that are appropriately scaled, prospective, controlled, randomized
clinical trials to obtain longitudinal data on the effect of DBS on cognition
and mood, and to examine the difference of stimulation on various targets.

O Studies, including the development of models, to further refine the
understanding of the functional organization of basal ganglia and its circuits
and their role in the control of behavior, including planned movement.

O Studies of the mechanisms of action of DBS, including local and distant
alterations such as, respectively,  micro-physiological changes occurring at
the electrode tip and changes in the neural networks.

O Studies of the effect of short and long term stimulation on motor control

O The development of improved and more versatile implantable microelectrodes
and stimulators to provide more somatotopic and focal information that is
better customized for certain regions.   

O The development of microelectrodes that can simultaneously stimulate and
record, do microdialysis, or infuse chemicals.

O The development of smaller, multiple-site electrodes, that can stimulate and
record from different brain structures simultaneously, such as the subthalamic
nucleus and the globus pallidus.

O The development of stimulators that are rechargeable and that have a wider
range of frequencies, voltages, and pulse widths, and that might provide
random pulses.

O The design of better methods of placing electrodes that reduce placement
time, expense, and morbidity, and increase accuracy.

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 in cells
and circuits including plasticity of synaptic connections, modulation of gene
expression, and the influences of activity on trophic factor release and

O The development of rodent models to study the behavioral manifestations of
different movement disorders and for acute drug screening.

O Studies of the purported neuroprotective effect of long-term DBS.

O Studies to compare DBS with surgical ablation in earlier stage Parkinson's
disease patients and in less compromised Parkinsonian animal models.

O Clinical and basic studies to determine the effect of DBS on symptoms that
are resistant to treatment with levodopa or dopaminergic drugs.

O Studies to examine the effects of DBS on the treatment of other neurological
problems, including pain, epilepsy, spinal cord injury, traumatic brain
injury, and stroke, and psychiatric disorders related to Parkinson's disease.

O Studies of the ethical issues in proposing surgery for earlier stage
patients who presently are adequately treated by drugs.


Annual Meeting:  Synthesis of the component projects of the consortium will
require multidisciplinary collaboration and communication of research results
and opportunities.  To facilitate such interactions, the NINDS 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 
participating in the annual meeting should be built into the proposed budget.

Collaborative Studies: The consortium structure is put in place to facilitate
collaboration among investigators. A mission of the consortium is to foster
joint collaborative initiatives among members. To this end, a Steering
Committee composed of the NINDS 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.


It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23,
No. 11, March 18, 1994.


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 is scientific or ethical reasons not to include them.  This
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


Prospective applicants are asked to submit, by November 15, 1999 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
Institute staff to estimate the potential review workload and avoid conflict
of interest in the review.

The Letter of Intent is to be sent to:

Eugene J. Oliver, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center
6001 Executive Blvd., Room 2203
Bethesda, MD 20892-9525


The Research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research; from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
Room MSC 7910, Bethesda, MD 20892, telephone 301/710-0267;email:

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.  In addition, the RFA label
available in the PHS 398 (rev. 4/98) application form must be affixed to the
bottom of the face page of the application.  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.   

The sample RFA label available at: has been modified to
allow for this change.  Please note this is in pdf format.

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 Institute
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for these grants, with the modifications noted below.


Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. (Applications that request
more than $250,000 direct costs in any year must follow the traditional PHS398
application instructions.)The total direct costs must be requested in
accordance with the program guidelines and  the modifications made to the
standard PHS 398 application  instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

4 of the PHS 398. It is not required and will not be accepted with the

categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See for sample
pages.) At the top of the page, enter the total direct costs requested for
each year.  This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount.  Include the Letter of
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by  
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for all
key personnel, following the instructions below. No more than three pages may
be used for each person. A sample biographical sketch may be viewed at:

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the type
of agreement and the date. All appropriate exclusions must be applied in the
calculation of the F&A costs for the initial budget period and all future
budget years.

o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review. 

Submit a signed, typewritten original of the application, including the
Checklist, and three If they only want one copy we should get 4; or we can get
three copies and they get two signed photocopies, in one package to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

In order to facilitate the review of applications, please mail or deliver one
copy of the application when completed to:

Dr. Lillian Pubols
Chief, Scientific Review Branch, NINDS, NIH
Neuroscience Center 
6001 Executive Blvd., Room 3208
Bethesda, MD 20892-9525       

Applications must be received by February 16, 2000.  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.


Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by NINDS.  Incomplete applications will be returned to the
applicant without further consideration.  As part of the initial merit review,
all applications will receive a written critique, undergo a process in which
only those applications deemed to have the highest scientific merit (generally
the top half of the applications received for review) will be discussed,
assigned a priority score, and receive a second level review by the NINDS
Advisory Council. What about NIA Council?  The next sentence should be
deleted.  Site visits are not anticipated for these Center grant applications.


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 review, comments on the following aspects of the application will
be made 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 the assignment of the overall score.

(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


Funding decisions will primarily be based on scientific and technical merit as
determined by the Initial Review Group, review by the National Advisory
Neurological Disorders and Stroke Council and by the National Advisory Council
on Aging, and the availability of funds. In selection of applications for
award, consideration will also be given to the need for program balance across
the areas of research outlined in this RFA.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Eugene J. Oliver, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center 
6001 Executive Blvd., Room 2203
Bethesda, MD 20892-9525
Telephone:     301/496-5680
FAX:      301/480-1080

William 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
Telephone:     301/496-1447
FAX:      301/480-1080

Judith A. Finkelstein, Ph.D.
Sensory/Motor Disorders of Aging Program
Neuroscience and Neuropsychology of Aging
National Institute on Aging
Gateway Building, Suite 3C307
7210 Wisconsin Avenue
Bethesda  MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (3020 496-1494

Direct inquiries regarding fiscal matters to:

Kimberly Pendleton
Grants Management Specialist
Grants Management Branch, DEA
Neuroscience Center
6001 Executive Blvd., Room 3254
Bethesda, MD 20892-9525
Telephone:  (301) 496-9231
FAX:  301-402-0219

Joe Ellis
Grants and Contracts Management Office
Gateway Building, Suite 2N212
7201 Wisconsin Avenue
Bethesda  MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672


This program is described in the Catalog of Federal Domestic Assistance No.
93.853 and 93.866.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law
99-158, 42 USC 241 and 285) 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 and contract 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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