Release Date:  July 27, 2001

RFA:  RFA-NS-02-009

National Institute of Neurological Disorders and Stroke
National Institute of Mental Health
National Institute of Aging
National Institute on Deafness and Other Communication Disorders
National Institute on Drug Abuse

Letter of Intent Receipt Date:  September 30, 2001
Application Receipt Date:       November 28, 2001


Functional brain imaging techniques that take advantage of the changes in 
hemodynamic responses of the brain (positron emission tomography, functional 
magnetic resonance imaging, and infrared imaging) have emerged as promising 
new avenues for studying the neural basis of many different cognitive 
activities. The National Institute of Neurological Disorders and Stroke 
(NINDS),the National Institute of Mental Health (NIMH), the National Institute 
on Aging (NIA), the National Institute on Deafness and Other Communication 
Disorders (NIDCD), and the National Institute on Drug Abuse (NIDA) invite 
research grant applications that offer the promise of exceptional technical 
and conceptual advances in our understanding of the nature of the signal being 
recorded in hemodynamic brain imaging techniques. We currently have a 
fundamental gap in our knowledge, because we do not truly understand the 
linkage between the hemodynamic response that is being recorded in imaging 
techniques and the supporting cellular and molecular mechanisms. Furthermore, 
the time course of the hemodynamic response, which evolves over 10 to 15 
seconds, has been problematic in the ability of these functional imaging 
techniques to be applied to issues involving temporal sequencing of various 
cognitive events.  Of particular interest for this RFA would be approaches 
involving functional imaging and neurophysiological (e.g., single and multi-
unit recording) studies conducted entirely in non-human primates intended to 
address the issue of the neural mechanisms underlying functional activation 
determined using fMRI or PET techniques. Also of interest are proposals that 
take advantage of improved understanding of the link between hemodynamic and 
neural events to increase the ability of functional imaging methods to 
accurately assess the temporal sequencing of cognitive activation that cannot 
be answered in humans with current technology. Thus, this RFA seeks proposals 
that will increase the utility of functional imaging techniques by a) 
providing greater understanding of the link to underlying neural activity and 
b) improving the ability of these techniques to address questions with a 
significant temporal component.  

In addition to understanding the fundamental physiological processes 
underlying the signals used in functional brain imaging, it is also critical 
to recognize that coupling between neuronal activity and blood flow is subject 
to modulation.  Among the largest sources of such modulation are the direct 
effects of drugs and endogenous neurotransmitters, especially catecholamine, 
on cerebrovascular function.  Such effects can constitute a major confound in 
studies in which pharmacological agents are administered and studies of 
populations who routinely take drugs, either for recreational or therapeutic 
reasons.  Examples include cocaine’s effects on heart rate and 
vasoconstriction, dopaminergic D1 receptor modulation of cerebral vasculature, 
and opioid effects on respiration.  Applications are encouraged that propose 
to study not only the magnitude and extent of drug and endogenous transmitter 
modulation of the hemodynamic functional imaging signal, but also development 
of methods and procedures for improving interpretation of functional imaging 
data when such confounding effects are present.



A central characteristic resulting from certain neurological disorders, mental 
illness, and drug abuse is a dysfunction of cognitive processes.  The 
systematic study of normal cognitive processes in humans and animals is vital 
to understanding these disorders.  In recent years, the development of non-
invasive functional brain imaging techniques has offered new opportunities for 
studying the neural control, representation and expression of cognitive 
functions in the alert, normal human.  Both positron emission tomography (PET) 
and functional magnetic resonance imaging (fMRI) techniques have been used 
extensively to investigate cognitive function. More recently, optical 
spectroscopy has been adapted for noninvasive imaging of human brain function 
as well. Although these techniques have provided an opportunity to ask 
questions concerning the neural correlates of cognitive function, limitations 
in their temporal and spatial resolution have led to constraints on the 
specific nature and the design of the experimental questions that can be 

Use of these techniques has led to many studies of the role of various brain 
areas in attention, perception, language processing and generation, learning 
and memory mechanisms, and emotion. An important issue in the interpretation 
of these studies has been the relationship between the specific measurement 
made (e.g., blood oxygenation/deoxygenation for the blood oxygenation level-
dependent (BOLD) fMRI technique, cerebral blood flow for the O15 labeled PET 
technique or the change in absorption of photons of particular wavelengths in 
intrinsic optical signals) and the neural activity hypothesized to underlie 
these changes. As neuroscience research increasingly focuses on the specific 
brain loci relevant to the pathology of various diseases and the underlying 
basis of various cognitive functions, it is increasingly important to 
determine the actual functional relationship between the images generated by 
these tools and the underlying neural activity in the relevant areas of the 
central nervous system.  

Objective and Scope:

The aim of this RFA is to solicit proposals that will increase the utility of 
functional imaging techniques for addressing questions relevant to the field 
of cognitive neuroscience by providing greater understanding of the link 
between hemodynamic effects and underlying neural activity and by improving 
the ability of these techniques to address questions with a significant 
temporal component.  There are several assumptions fundamental to this RFA.  
First, addressing these questions in a suitable way requires the use of 
nonhuman primate or other animal model systems.  Second, the continued use and 
further development of functional neuroimaging techniques are key to advancing 
our understanding of the mechanisms of human cognition.  Third, a more precise 
understanding of the relationship between neuronal activity and the generation 
of hemodynamic responses detected by the various imaging techniques are 
necessary and important step in expanding the breadth of understanding and 
scientific knowledge which can be gained from using these experimental 
techniques.  Finally, the ability to determine the temporal patterns of 
activation, or more precisely to infer the dynamics of the neuronal activation 
that underlies the patterns of hemodynamic changes, is similarly important.  

These assumptions give rise to more specific questions: To what extent can one 
infer the temporal sequence of patterns of synaptic activation from imaging 
data?  Can one define a functional relationship between the level of 
activation measured with imaging technology and the presumed level of 
underlying neuronal activation?  What are the limits in precision, using 
current imaging technology, for answering these questions?  What can be done 
to increase the precision of these techniques and how does this increase the 
breadth and level of detail possible in studies of the neural basis of 
cognitive function? Within the limits of the current technology, how can more 
precise information concerning the neural basis of cognitive function and its 
dynamics be obtained?  How can the combination of neuroimaging and in vivo 
electrophysiological or neurochemical techniques in awake, behaving nonhuman 
primates improve our understanding of cognitive function?

These questions define a need to understand, at a methodological level, the 
relationship between neuronal activation and the detection of a region of 
functional activation as described by a specific neuroimaging technique.  
Although groundbreaking in its origin, the task-dependent linking of increased 
activation to specific brain regions, which has been the hallmark of earlier 
neuroimaging studies, is ultimately limited in its explanatory power.  As the 
neuroimaging techniques have evolved and newer designs (e.g., single-trial or 
event-related fMRI) have been implemented, the potential explanatory and 
heuristic value of these techniques has grown, allowing more sophisticated 
questions to be asked and answered about the dynamics of cognitive function. 

This RFA seeks a range of proposals focused on understanding the relationship 
between the signals measured using standard brain imaging techniques and the 
underlying neural activity.  Because functional imaging techniques currently 
are used extensively to study cognitive function in humans, the 
characterization of this relationship is imperative for the analysis, 
interpretation, and understanding of brain activational patterns during 
cognitive activity. Examples of potential research questions would include but 
not be limited to issues such as:
o  Studies exploring the relationships between synaptic activity (both 
excitatory and inhibitory), brain metabolic changes, vascular responses and 
hemodynamic signals in cortical and subcortical regions.
o  Studies establishing a quantitative link between neuronal responses and 
fMRI signals – relationships of hemodynamic signal to neuronal firing rates 
and neuronal subthreshold activity.
o  Imaging and standard electrophysiological studies addressing the issue of 
spatial homogeneity, sensitivity and variability due to region specific 
vasculature and neuronal packaging.
o  Studies coupling the MRI technique with other modes of investigation that 
would directly rule out alternative sources of signal change.  Specifically, 
studies that develop methods to assess or account for changes in vasculature, 
circuitry, and/or structure that may occur, for example, with normal aging or 
neurodegenerative disease, that would allow the production of unbiased 
measures of functional activation.
o  Studies combining the techniques of functional neuroimaging with in-vivo 
single unit electrophysiology or microdialysis in nonhuman primates.
o  Studies demonstrating direct coupling between electrical activity (EEG – 
MEG) and hemodynamic signals (MRI – optical signal).
o  Development and validation of regionally specific computational models of 
electrical activity and hemodynamic/metabolism in nonhuman primates or other 
relevant animal models. Computational and modeling approaches should include a 
physiological component within the same research project. 
o  Development and adaptation of novel experimental designs employing existing 
functional imaging techniques in humans, to nonhuman primate or other relevant 
models for the purpose of extending these protocols to studies linking 
neuronal activity to hemodynamic signal to specifically address the issue of 
the dynamics of cognitive function.


The NIH is interested in ensuring that the research resources developed 
through this RFA become readily available to the research community for 
further research, development, and application, in the expectation that this 
will lead to knowledge of benefit to the public. For applications in response 
to this RFA, there are two special requirements regarding research resources 
produced in the proposed project:

(1) Applications must include a specific plan by which they will share 
research resources with the wider scientific community.

(2) Applications must include a plan addressing if, or how, they will 
exercise their intellectual property rights while making available to 
the broader scientific community patentable research resources (e.g. 
validation tools, software for data sharing, specialized tools for the 
integration of imaging and electrophysiological data). 

Post-Award Management

During the course of the award period, the Principal Investigators may be 
invited to meet with NIH staff to review and share scientific progress. Other 
scientists external to and knowledgeable about these studies also may be 
invited to participate. Some of the meetings should be organized by the PIs, 
whereas the NIH may organize others. Application budget requests should 
include travel funds for the Principal Investigator to attend two meetings a 
year in the metropolitan Washington, D.C. area.


This RFA will use the National Institutes of Health (NIH) individual research 
project 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 for an application submitted in response 
to this RFA must 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 July 1, 2002.


The participating Institutes intend to commit approximately $5,250,000 in FY 
2002 for this RFA. An applicant may request a project period of up to five 
years. Because the nature and scope of the research proposed might 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. *Note $750,000 (NIA), $500,000(NIDCD) and 
$1,000,000 (NIDA) of the funds committed for this RFA will only be paid for 
meritorious applications relevant to the mission of these Institutes. Although 
NIAAA is not currently providing funds to this RFA, the Institute is also 
willing to support meritorious applications received in response to this RFA 
that are relevant to their mission. 


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, and 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 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:

Emmeline Edwards, Ph.D.
Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 2109
Bethesda, MD  20892-9521
Telephone:  (301) 496-9964
FAX:  (301) 402-2060

Kevin Quinn, Ph.D.
Behavioral and Integrative Neuroscience Research Branch
National Institute of Mental Health
6001 Executive Blvd., Room 7N-7168
Bethesda, MD 20892-9637
Telephone: (301) 443-1576
FAX: (301) 443-4822

Molly V. Wagster, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Ave.
Gateway Bldg., Suite 3C307
Bethesda, MD  20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494

Lynn E. Luethke, Ph.D.
Scientific Programs Branch
National Institute on Deafness and Other Communication Disorders
6120 Executive Blvd, MSC 7180
Bethesda, MD 20892-7180
Phone: (301) 402-3458
FAX: (301) 402-6251

Thomas G. Aigner, Ph.D.
Division of Neuroscience and Behavioral Research
National Institute on Drug Abuse
6001 Executive Blvd., Room 4282 MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 435-1314
FAX: (301) 594-6043

Direct inquiries regarding review issues to:

Lillian Pubols, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 3208
Bethesda, MD 20892
Telephone: (301) 496-9223
FAX: (301) 402-0182

Direct inquiries regarding fiscal matters to:

Ken Bond
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 3290
Bethesda, MD  20892
Telephone: (301) 496-9231
FAX:  (301) 402-0219

Diana S. Trunnell
Assistant Chief, Grants Management Branch
National Institute of Mental Health
6001 Executive Blvd., Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
FAX: (301) 443-6885
Linda Whipp
Chief, Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Ave.
Gateway Bldg., Suite 2N212
Bethesda, MD  20892-9205
Telephone :  (301-496-1472
Fax : (301) 402-3672

Sara Stone
Chief, Grants Management Branch
National Institute on Deafness and Other Communication Disorders
6120 Executive Blvd, MSC 7180
Bethesda, MD 20892-7180
Phone: (301) 402-0909
FAX: (301) 402-1758

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Blvd., Room 3131, MSC 9541
Bethesda, MD 20892-9541
Telephone: (301) 443-6710
FAX: (301)- 594-6847

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.

Prospective applicants are asked to submit, by September 30, 2001, a letter of 
Intent to be sent to: 

Emmeline Edwards, Ph.D.
Program Director
Systems and Cognitive Neuroscience
National Institute of Neurological disorders and Stroke
6001 Executive Blvd, Room 2109
Bethesda, MD 20892
Tel: 301-496-9964
Fax: 301-402-2060


Letter of Intent Receipt Date:    September 30, 2001
Application Receipt Date:         November 28, 2001
Peer Review Date:                 March 2002
Council Review:                   May 2002
Earliest Anticipated Start Date:  July 2002


The PHS 398 research grant application instructions and forms (rev. 5/2001) 
available at 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 301/710-0267, Email:

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:

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

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 Pubols, Ph.D.
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 3208
Bethesda, MD 20892
Rockville, MD 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.

Appendices are to be sent directly to Dr. Pubols at the above address. 
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.


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 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  
Additional information about Modular Grants is also available on this site.


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

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, NIMH, NIA, NIDCD and NIDA National Advisory Councils. 

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 

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 

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.

o The adequacies of the proposed plan to share data.  This is a specific 
requirement of the RFA.


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, and program balance


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.


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:


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:

Applicants may wish to place data collected under this RFA 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. 


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), 
Cognitive Neuroimaging: Understanding The Link Between Neuronal Activity And 
Functional Imaging Signals, 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 Nos. 
93.853 (NINDS), 93.242 (NIMH), 93.866 (NIA), 93.847 (NIDCD), 93.279 (NIDA).  
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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