FUNCTIONAL MRI AND INTERVENTION FOR COGNITIVE DEFICITS AFTER TRAUMATIC BRAIN INJURY 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 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE 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 functioning. RESEARCH OBJECTIVES Background 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 outcomes. 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. Scope 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 survival. 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 function. 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. MECHANISM OF SUPPORT 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 2001. 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 http://grants.nih.gov/grants/guide/notice-files/not98-030.html 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 http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE 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. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to : 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 Email: mm108w@nih.gov 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 Email: rn21e@nih.gov 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 jr3e@nih.gov 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 Email: lp28e@nih.gov 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 Email: rr46w@nih.gov 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 Email: mc113b@nih.gov 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 Email: dt21a@nih.gov LETTER OF INTENT 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 E-mail: mm108w@nih.gov SCHEDULE SUMMARY 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 APPLICATION PROCEDURES 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 301/435-0714, email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and 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. BUDGET INSTRUCTIONS 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. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete 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 http://grants.nih.gov/grants/funding/modular/modular.htm 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: http://grants.nih.gov/grants/funding/modular/modular.htm - 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 marked. There is a sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf in pdf format. 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: 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. REVIEW CONSIDERATIONS 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 support? In addition to the above criteria, in accordance with NIH policy, all individual scientific projects will be reviewed with respect to the following: 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their 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: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. 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 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. 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), " 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 http://www.health.gov/healthypeople. AUTHORITY AND REGULATION 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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