Release Date:  June 29, 2000

RFA:  NS-01-007

National Institute of Neurological Disorders and Stroke
National Institute of Child Health and Human Development
National Institute of Mental Health

Letter of Intent Receipt Date:  December 15, 2000
Application Receipt Date:       February 15, 2001



Traumatic brain injury (TBI) is a prevalent and dangerous occurrence in the 
United States, with approximately 2 million new cases each year.  It is the 
leading cause of mortality in persons under 45 years old, and a leading cause 
of disability in all age groups.  In adult age groups (ages 21-55) a moderate 
or even "mild" TBI can result in lifelong deficits in cognition, behavior, 
and emotional stability that can be described as decreased executive 
functioning.  Such problems impair employment, disrupt stable social 
relationships and can isolate the individual to a narrow world of disability 
and reduced opportunity.  Researchers have defined many pathological events 
that occur in the brain early after a TBI, and are beginning to define 
behavioral consequences in more chronic periods, but the underlying 
neurobiology for the deficits in executive functioning have not been defined.  
Strategies to overcome the long-term consequences of TBI include cognitive-
behavioral intervention, pharmacological management, assistive technology, 
environmental manipulation, education and counseling.  Little research has 
been done on the efficacy of these approaches.  Use of functional imaging to 
evaluate the circuitry involved in the cognitive/behavioral aspects of 
executive function in TBI may reveal insights that could be applied to the 
evaluation of such attempts at treatment.  Therefore, the NINDS, the National 
Center for Medical Rehabilitation Research in  NICHD, and NIMH seek research 
devoted to functional imaging of brain activity in brain-injured individuals 
with complex cognitive deficits that constitute altered executive 



Imaging studies of the brain have been responsible for advances in the 
treatment of many aspects of brain function, as well as in understanding the 
functional loci of many neurological disorders.  In TBI, imaging has been 
very useful in the diagnosis and development of management strategies and in 
the acute stages after injury.  In acute and sub-acute stages, CT and MRI 
have revealed unsuspected diffuse injuries in various regions throughout the 
brain.  Knowledge of this pathophysiology has lead to new experimental 
approaches to reduce secondary damage that could affect both short-term and 
long-term outcome.  It is likely that additional studies in functional 
imaging will help to unravel the long-term consequences of TBI, and aid in 
further diagnosis, treatment and rehabilitation.

Of particular concern after head injury are changes in cognition, memory, 
attention and emotion that combine into a little-studied area of 
neuropsychology termed executive function.  Behavioral and/or pharmacological 
intervention programs that seek to allow injured individuals to return to 
work, recreation, school, and society are costly, complicated, and often of 
only limited success.  Better characterization and definition of the brain 
regions and functional deficits may improve patient diagnosis and refine 
strategies for intervention.

Functional MRI is a relatively widespread method that  allows visualization 
of brain biochemistry, metabolism, and anatomy.  In addition, data has and is 
being accumulated from normal subjects and from various populations of 
special psychological or psychiatric disorders that will allow comparison to 
images seen from TBI studies.  Images could then be used to identify areas 
damaged by specific head injuries, and the types of long-term changes in the 
brain that occur with or without intervention or rehabilitation.  Correlating 
functional imaging data with other cognitive, behavioral, or 
neuropsychological outcomes will help in the design of new strategies for 
assessment of rehabilitation of persons with TBI.  Programs of remediation 
that target specific difficulties based on this information could be designed 
with outcomes defined both in terns of neurobiological and functional 

Such studies will require cooperation and collaboration among several 
disciplines including the design and interpretation of fMRI studies, 
neuropsychological assessment, neurological evaluation of TBI, experimental 
design and statistical analysis, rehabilitative strategies, theories of 
neuroplasticity, and behavioral interventions.


Applications in response to this RFA will involve collaborative studies that 
apply fMRI to assess the neurological deficits that accompany changes in 
executive functioning after TBI.  Studies that correlate functional imaging 
with other assessments of outcome (i.e., neuropsychology, depression or other 
psychiatric sequelae, activities of daily living, or improved quality of 
life) are especially encouraged.  Plasticity within the injured brain, or the 
use of other regions and complementary strategies to accomplish tasks, could 
either facilitate or inhibit recovery and rehabilitation.  At this time, 
little is known about the possible correlation of alterations in imaging 
patterns with dysfunction produced by TBI, or about the effects of training 
strategies for TBI-induced deficits on brain structure and function.  It is 
important to know if specific strategies can induce, alter, or redirect 
functional patterns within the damaged brain, and if those changes are 
reflected in neuropsychological or behavioral outcome measures.

Because of the specific needs of pediatric and adult head injury populations, 
and the confounding variables associated with the developmental process in 
children of different ages, this RFA will limit the study population to 
persons over 21 years of age who have sustained a head injury after the age 
of 18 years.  It is anticipated that the populations under study will range 
in age throughout the adult years, and at varying times of post-injury 

Research areas of interest include, but are not limited to:

o Prospective studies using fMRI to follow changes in activation in the 
injured brain during sub-acute and chronic stages.  These studies should 
include appropriate control subjects to assess strategies of task acquisition 
after TBI.
o Use of fMRI to correlate brain activity/structure in TBI with specific 
cognitive deficits within the domain of executive function after TBI.  Of 
particular interest are patterns of involvement of prefrontal and limbic 
cortices in memory, attention, insight, processing speed, and integrative 
tasks that contribute to executive function.  
o Assessment of the patterns of activation within the limbic system, 
including the limbic lobe of the cortex, as well as associated sub-cortical 
nuclei (amygdaloid complex, septal nuclei, hypothalamus, epithalamus, 
anterior thalamic nuclei, and basal ganglia) in deficits involving executive 
o Use of functional imaging to assess changes and localize activity in 
specific brain regions (i.e. frontal/parietal/temporal cortex, right and left 
hemispheres, cerebellar activation, diffuse versus focal patterns) during 
cognitive activities in persons with cognitive deficits after TBI.
o Studies to help understand the particular vulnerability of regions that 
contribute to executive function, and the pathophysiological mechanisms that 
contribute to these deficits.
o Studies to monitor the longitudinal changes in brain regions that directly 
contribute to TBI deficits in executive function, as well as evaluating the 
therapeutic effects of behavioral, pharmacological, and other therapeutic 
interventions.  Study designs may include multiple imaging strategies, 
varying levels of difficulty in task design, assessment of levels of skill, 
or other methods to delineate brain network activity patterns in TBI patients 
versus appropriate control subjects.
o Use of functional imaging to assess changes in activation of brain regions 
after specific interventions directed at memory, attention, concentration, 
comprehension, insight, or other components of executive/cognitive function.  
o fMRI studies to help evaluate current treatment and rehabilitation 
strategies and test their efficacy
o Studies to develop and validate surrogate markers based on fMRI to monitor 
progress in TBI as related to executive function.


This RFA will use the National Institutes of Health (NIH) individual research 
grant (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 of an application submitted in response to this RFA may 
not exceed five 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 anticipated award date is September 

In accordance with NIH policy, investigators planning to submit an 
application requesting $500,000 or more in direct costs for any year are 
advised that they must contact the NINDS program officer listed under 
INQUIRIES before submitting the application, i.e., as plans for the study are 
being developed.  Furthermore, the applicant must obtain agreement from staff 
that the NINDS will accept the application for consideration for award.  The 
applicant must identify, in a cover letter sent with the application, the 
staff member at NINDS who agreed to accept assignment of the application.  
Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at

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 NINDS, NICHD, and NIMH intend to commit a total of approximately $4.0 
million in FY 2001 to fund eight to ten new and/or competitive continuation 
grants in response to this RFA.  Applicants may request a project period of 
up to five years.  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 NINDS, NICHD and NIMH 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. 


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 


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 :

Mary Ellen Cheung, Ph.D.
Injury and Plasticity Program
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2206, MSC 9525
6001 Executive Boulevard
Bethesda, Maryland 20892-9525
Telephone: (301) 496-1447

Ralph M. Nitkin, Ph.D.
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 2A03
Bethesda, Maryland 20892-7510
Telephone: (301) 402-4206

Judith M. Rumsey, Ph.D.
Division of Neuroscience and Basic Behavioral Research
National Institute of Mental Health
6001 Executive Blvd., Room 7175, MSC 9643
Bethesda, MD 20892-9643
Telephone: (301) 443-1692

Direct inquiries regarding review issues to:

Lillian M. Pubols, Ph.D.
Director, Division of Scientific Review 
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Suite 3208
Rockville, Maryland 208512
Telephone: (301) 496-9223

For fiscal and administrative inquires regarding the announcement, potential 
applicants may write or call:

Ms Rita Rollins-Hickey
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 3254
6001 Executive Boulevard
Bethesda, Maryland 20892
Telephone: (301) 496-7488

Ms. Mary Ellen Colvin
Grants Management Branch
National Institute of Child Health and Human Development
Building 61E, Room 8A17G, MSC 7510
6100 Executive Boulevard
Bethesda, MD 20892-7510
Telephone: 301-496-1304

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: 301-443-6885


Prospective applicants are asked to submit, by December 15, 2000 , 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.  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 should be sent to:

Mary Ellen Cheung, Ph.D.
Neuroscience Center, Suite 2209, MSC 9525
6001 Executive Boulevard
Rockville, Maryland 20852 (courier service)
Bethesda, Maryland 20892-9525 (surface mail)
FAX: (301) 480-1080

Letter of Intent Receipt Date:    December 15, 2000
Application Receipt Date:         February 15, 2001
Peer Review Date:                 May, 2001
Council Review:                   September, 2001
Earliest Anticipated Start Date:  September, 2001


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 and from the Division of Extramural Outreach 
and Information Resources, National Institutes of Health, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: 


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 


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 PHS 398 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.

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.

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.  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 

There is a sample RFA label available at: in pdf format.

Submit a signed typewritten original of the application, including the 
checklist, and three signed photocopies, in one package to:

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:

Dr. Lillian Pubols
Director, Division of Scientific Review 
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Suite 3208
Rockville, Maryland 20852 (for express/courier service)

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.


Upon receipt, applications will be reviewed for completeness by the CSR and 
for responsiveness by institute staff.  If the application is not responsive 
to the RFA, CSR staff may contact the applicant to determine whether to 
return the application to the applicant or submit it for review in 
competition with unsolicited applications at the next review cycle.

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 NINDS in accordance with the 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, NICHD, or NIMH 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 each project in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals. Each 
of the criteria listed below will be addressed and considered in assigning 
the score for a research project, weighting them as appropriate for each 
project. Note that the project 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. In their evaluations, reviewers will comment on:

(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 

In addition to the above criteria, in accordance with NIH policy, all 
individual scientific projects will be reviewed with respect to the 

o The adequacy of plans to include both genders, minorities and their 
subgroups 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: 1) scientific and technical merit as determined by peer review; 2) 
availability of funds; and 3) programmatic priorities.


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 are 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 was published in the Federal Register of March 28, 1994 (59 
FR 1450814513) and in the NIH Guide for Grants and Contracts, Volume 23, 
Number 11, March 18, 1994., available on the web at:


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 

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.

Because of the specific needs of pediatric and adult head injury populations, 
and the confounding variables associated with the developmental process in 
children of different ages, this RFA will limit the study population to 
persons over 21 years of age who have sustained a head injury after the age 
of 18 years.  It is anticipated that the populations understudy will range in 
age throughout the adult years, and at varying times of post-injury survival.


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 sued 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.


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), " Functional MRI and Intervention for Cognitive Deficits 
after Traumatic Brain Injury", is related to one or more of the priority 
areas.  Potential applicants may obtain a copy of "Healthy People 2010" at


This program is described in the Catalog of Federal Domestic Assistance No. 
93.853, 93.929, and 93.242. Awards are made under authorization of the Public 
Health Service Act, as amended (42 USC 241 and 284) and administered under 
PHS 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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