RFA-NS-02-009: COGNITIVE NEUROIMAGING: UNDERSTANDING THE LINK BETWEEN NEURONAL ACTIVITY AND FUNCTIONAL IMAGING SIGNALS

Department of Health
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COGNITIVE NEUROIMAGING: UNDERSTANDING THE LINK BETWEEN NEURONAL ACTIVITY AND FUNCTIONAL IMAGING SIGNALS Release Date: July 27, 2001 RFA: RFA-NS-02-009 National Institute of Neurological Disorders and Stroke (NINDS, http://www.ninds.nih.gov/) National Institute of Mental Health (NIMH, http://www.nimh.nih.gov/) National Institute of Aging (NIA, http://www.nih.gov/nia/) National Institute on Deafness and Other Communication Disorders (NIDCD, http://www.nidcd.nih.gov/) National Institute on Drug Abuse (NIDA, http://www.nida.nih.gov/) Letter of Intent Receipt Date: September 30, 2001 Application Receipt Date: November 28, 2001 PURPOSE 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. RESEARCH OBJECTIVES Background: 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 asked. 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. SPECIAL REQUIREMENTS 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. MECHANISM OF SUPPORT 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. FUNDS AVAILABLE 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. ELIGIBILITY REQUIREMENTS 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 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 Email: ee48r@nih.gov 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 Email: kquinn@mail.nih.gov 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 Email: wagsterm@nia.nih.gov 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 Email: lynn_luethke@nih.gov 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 Email: ta17r@nih.gov 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 Email: lp28e@nih.gov 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 Email: bondk@nih.gov 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 E-mail: Diana_Trunnell@nih.gov 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 Email: whippl@nia.nih.gov 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 Email: stones@mail.nih.gov 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 Email: gf6s@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. 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 Email: ee48r@nih.gov SCHEDULE SUMMARY 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 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 301/710-0267, Email: GrantsInfo@nih.gov. 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 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. 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. REVIEW CONSIDERATIONS 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 consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NINDS in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the 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 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. o The adequacies of the proposed plan to share data. This is a specific requirement of the RFA. 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, and program balance 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 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), 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 http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS 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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