Department of Health and Human Services


Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Mental Health (NIMH)
National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title

Temporal Dynamics of Neurophysiological Patterns as Potential Targets for Treating Cognitive Deficits  in Brain Disorders (R21)

Activity Code

R21 Exploratory/Developmental Research Grant

Announcement Type

New

Related Notices
  • June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number

PAR-14-158

Companion Funding Opportunity

PAR-14-153, R01 Exploratory/Developmental Grant

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.242, 93.853 

Funding Opportunity Purpose

A rich body of evidence suggests that cognitive processes are associated with particular patterns of neural activity. These data indicate that oscillatory rhythms, their co-modulation across frequency bands, spike-phase correlations, spike population dynamics, and other patterns might be useful drivers of therapeutic development for cognitive improvement in neuropsychiatric disorders.  This initiative encourages applications to test whether modifying electrophysiological patterns during behavior can improve cognitive abilities.  Applications should use experimental designs that incorporate active manipulations to address at least one, and ideally more, of the following topics: (1) in behaving animals, determine which parameters of neural coordination, when manipulated in isolation, improve particular aspects of cognition;  (2) in animals or humans, determine how particular abnormalities at the cellular or molecular level, such as specific receptor dysfunction, affect the coordination of electrophysiological patterns during behavior;  (3) determine whether in vivo, systems-level electrophysiological changes in behaving animals predict analogous electrophysiological and cognitive improvements in normal humans or clinical populations; and (4) use systems-level computational modeling to develop a principled understanding of the function and mechanisms by which oscillatory and other electrophysiological temporal dynamic patterns unfold across the brain (cortically and subcortically) to impact cognition.

The R21 grant mechanism is specifically intended to encourage new exploratory and developmental research projects. These studies should break new ground or extend previous discoveries toward new directions or applications. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel methodologies, tools, technologies, or interventions that could have a major impact on health research and practice. Unlike applications under the R01 mechanism, preliminary data are not required for R21 applications. Preliminary data may nonetheless be included if available.

Key Dates
Posted Date

March 14, 2014

Open Date (Earliest Submission Date)

May 16, 2014

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

Standard dates apply, by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Standard AIDS dates apply, by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Scientific Merit Review

Standard dates apply

Advisory Council Review

Standard dates apply

Earliest Start Date

Standard dates apply

Expiration Date

May 8, 2017

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


A compatible version of Adobe Reader is required for download. For Assistance downloading this or any Grants.gov application package, please contact Grants.gov Customer Support at http://www07.grants.gov/contactus/contactus.jsp.
Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement


Section I. Funding Opportunity Description

The R21 grant mechanism is specifically intended to encourage new exploratory and developmental research projects. These studies should break new ground or extend previous discoveries toward new directions or applications. These studies may involve considerable risk but may lead to a breakthrough in a particular area, or to the development of novel methodologies, tools, technologies, or interventions that could have a major impact on health research and practice. Unlike applications under the R01 mechanism, preliminary data are not required for R21 applications. Preliminary data may nonetheless be included if available.

Purpose

The purpose of this funding opportunity announcement (FOA) is to lay the groundwork for integrating systems-level neuroscience manipulations into the pipeline of treatment development for cognitive deficits in brain disorders.  A rich body of knowledge exists regarding the systems-level coordination of temporal dynamic patterns of electrophysiological activity in the brain.  One key principle that has emerged from basic systems-level neuroscience is that brain rhythms are necessary for normal cognition, including the co-modulation of rhythms across oscillatory frequency bands, spike-phase correlations, and spike population dynamics.  On the clinical side, cognitive symptoms have proven to be among the least tractable and most disabling problems across widely differing brain disorders, from autism and epilepsy to schizophrenia.  Almost none of the existing treatments for neuropsychiatric illnesses were designed with cognitive outcomes in mind.  Even for medications that are based on a rational understanding of single-gene disorders that strongly affect cognition, such as Fragile X, Rett, or Angelman syndromes, it has been difficult to substantially ameliorate cognitive symptoms in patients.  Therefore, it might be useful to address cognitive symptoms via a greater consideration of the neurophysiological patterns at the level of systems neuroscience, and whether these patterns can discern specific patient populations where a cognitive treatment could most effectively improve function, based on particular electrophysiological patterns.  However, in order to design the appropriate cognitive screening assays that encompass systems-level neuroscience for use in future drug development screening or clinical trial stratification, further research and validation of these measures are needed.  The purpose of this FOA is to encourage applications that use active manipulations to address at least one, and ideally more, of the following points:  (1) in behaving animals, determine which parameters of neural coordination, when manipulated in isolation, improve particular aspects of cognition;  (2) in animals or humans, determine how particular abnormalities at the cellular or molecular level, such as specific receptor dysfunction, affect the coordination of electrophysiological patterns during behavior;  (3) determine whether in vivo, systems-level electrophysiological changes in behaving animals predict analogous electrophysiological and cognitive improvements in normal humans or clinical populations; and (4) use systems-level computational modeling to develop a principled understanding of the function and mechanisms by which oscillatory and other electrophysiological temporal dynamic patterns unfold across the brain (cortically and subcortically) to impact cognition. 

Background

Cognition appears to emerge at the level of populations of neurons, with information represented and organized in the form of precise spike and network events that are temporally coordinated across brain areas.  For example, there have been notable advances in our basic understanding of the role of local field potential (LFP) oscillations and large-scale coordination of neural networks in learning and memory.  In rodents, particular patterns of temporal dynamics have been shown to proportionally improve or worsen working memory, and particular LFP oscillatory bands predict episodic/relational learning.  Theta phase precession is another well-known precise temporal code that might be required for optimal cognition, and the precise reactivation of neural activity during hippocampal sharp wave ripples is also a temporally coordinated representation that might be necessary for memory consolidation.  These types of findings should be expanded on within the field of learning and memory, as well as broadened to other areas of cognition such as attention and reasoning, and they can also be brought to bear on areas of translation such as pre-clinical target validation studies in animals or humans.  Work in non-human primates is also encouraged, as it would provide a bridge between rodent and human work.

In healthy humans, scalp electroencephalogram (EEG) oscillations in particular frequency bands change with memory-related performance, as well as with attentional demands.  Intracranial recordings in humans have also revealed phase-amplitude coupling during working memory; findings are emerging that direct brain stimulation parameters that impact these measures might be able to improve memory performance.  Non-invasive treatments aimed at altering rhythms have also begun to suggest a potential for therapeutic intervention, although the effects have been mixed.  It seems likely that we do not yet understand the underlying neural mechanisms well enough to manipulate them with sufficient precision to obtain a predictable outcome.  Nevertheless, since electrophysiological patterns appear to be required for normal cognition across rodents and primates, such patterns might be useful targets for the development and evaluation of novel treatments for cognitive enhancement.

From a disease standpoint, electrophysiological aberrations exist in many brain disorders, and recent findings in the study of a number of disorders suggest that modulating changes could potentially have appreciable benefits to the individual.  In schizophrenia, emerging findings suggest that systems-level electrophysiological endophenotypes are modifiable and that such modifications have the potential to improve cognition.  Similarly, various types of epilepsy are characterized by electrographic abnormalities that occur during and also between seizure events in patients and model animals.  Even non-seizure causing electrographic abnormalities in some cases appear to impact the normal, coordinated activity of networks subserving cognitive functions.  In autism, the modest amounts of electrophysiological data that exist in patients and model organisms suggest that this disorder also has disruptions in temporal coordination of neural signals, and that electrophysiological patterns at the level of neural populations might represent an intermediate, modifiable phenotype.  For instance, a tantalizing recent finding suggests that long-term, effective behavioral therapy in autism might shift EEG oscillations of patients into a more normal range.  Furthermore, recent and upcoming, rationally-developed pharmacological interventions are being tested for autism spectrum disorders, whose effect on temporal dynamics of electrophysiological patterns might be instructive to examine, especially if the treatments are directed at the cognitive impairments that lead to significant functional deficits for these patients.  It is fundamentally important to understand how deficits in electrophysiological signatures predict cognitive deficits and whether modifying these signatures can improve cognition.  The underlying hypothesis of this FOA is that cognitive dysfunction results, in part, from compromised systems-level electrophysiological patterns, that these patterns are necessary for cognition, and therefore, treatments that improve cognitive symptoms should aim to improve the underlying aberrant electrophysiological patterns.

Research Objectives

Applications should address at least one, and ideally more, of the following topic areas:  

Topic 1:  Temporal dynamics of neural patterns that impact cognition

In wildtype or model animals, determine which aspects of temporal coordination of systems-level neural activity affect particular forms of cognition such as working memory, long-term memory, relational/spatial processing, attention, cognitive control, decision making, or social cognition.  Projects should manipulate specific aspects of the electrophysiological patterns (e.g., the power of oscillatory frequencies during particular task periods, or the degree of phase-amplitude coupling of particular frequency pairs) to determine what parameters, if manipulated appropriately, might yield the most robust and reliable improvements in cognition.  A related question is whether any resulting behavioral improvements are proportional to particular changes in neural patterns, or whether this is a step function, and this might differ across types of cognition.  Active manipulations proposed in grant applications that address Topic 1 can consist of electrical or magnetic brain stimulation, optogenetics, pharmacological compounds including novel or existing medications if well justified, or other modalities.  Novel interventions are encouraged if they might provide greater temporal and/or spatial resolution.  It is expected that applications provide a strong scientific rationale for the specific biological intervention chosen, and why it is expected to selectively alter electrophysiological measures in a particular direction.  All projects must include measures of neural activity at the systems level during awake behavior.

Topic 2:  Understanding how molecular aberrations lead to systems-level discoordination

In animals or humans, understand how particular abnormalities at the cellular or molecular level, such as glutamate or GABA receptor dysfunction, affect the coordination of electrophysiological patterns during cognition.  Single-gene disorders in particular, such as Fragile X or Rett syndromes, might be a good opportunity to study such mechanistic questions in the context of systems level dynamics, but the case can also be made for neuropsychiatric disorders of more heterogeneous etiology.  The emphasis can be on discovering ways to rescue the systems-level discoordination with either molecular/cellular interventions (e.g., pharmacology, genomic interventions), or with in vivo neurophysiology manipulations (e.g., patterned electrical, optogenetic stimulation), but the outcomes should be measured at least at both the systems electrophysiology level and at the behavioral level.  The aberrations at the molecular/cellular level could be part of the underlying pathology of a particular disease or a consequence of an earlier insult that is no longer present. In any case, identification of the molecular determinants of systems-level discoordination will provide an opportunity for treatment development and assessment.

Topic 3:  Animal-to-human translation

Determine whether the changes in neural coordination patterns that improve cognition in animals predict analogous electrophysiological and cognitive improvements in normal humans and/or clinical populations.  The main goal is to understand the translational value of systems electrophysiology in pre-clinical models, to know whether an electrophysiological pattern identified in a relevant model system is predictive of a similarly aberrant pattern in patients, and whether the effects of any interventions in animals are predictive of their effects in humans.  A secondary goal is to characterize aberrant electrophysiological patterns during cognition in clinical patients, although electrophysiological recordings in humans must be accompanied by parallel work in animals that includes active interventions.  It is expected that, to the greatest extent possible, identical interventions (e.g., the same pharmacological compounds, or comparably patterned electrical stimulation in model animals and humans) and tasks (e.g., equivalent working memory tasks) will be used.  A related question of interest is whether any existing or novel medications are able to modify neural coordination patterns, and whether this mediates any improvement in cognition; this work must also be accompanied by mechanistic, parallel work in animals. 

Topic 4:  Computational modeling

Develop a computational model to allow a comprehensive, principled understanding of the function and mechanisms by which neural coordination patterns (cortical and subcortical) impact cognition.  There are two goals with this.  One goal is to reach a mechanistic understanding of how rhythmic patterns support information processing in the brain in the service of cognition, and, relatedly, what algorithms are being implemented in the brain for each type of cognition, including, but not limited to, spatial navigation, non-spatial relational processing (e.g., transitive inference), manipulation of items in working memory, etc.  A second goal is to understand how modifying a neural pattern in one region of the network affects the patterns in other brain regions, taking into account the underlying anatomy.  This work can include modeling how brain stimulation at the scalp might affect oscillations and information processing subcortically (e.g., in the hippocampus).  The purpose of this is to inform future therapeutic treatment development.  Applications can address one or more of these goals, and any computational modeling must include and be closely informed by experimental manipulations in animals or humans.

Examples of research topics that would be areas of interest include, but are not limited to:

In addition to addressing at least one of the four topic areas listed above, all applications under this FOA are also expected to fulfill the following requirements:

The work proposed under this FOA is considered pre-clinical; grant applications for clinical trials should be submitted under the appropriate Funding Opportunity Announcement.  This FOA seeks to generate a mechanistic understanding of what aspects of neural coordination and patterning can be modified to improve cognition.  A related goal is the identification of reliable and sensitive electrophysiological signatures that would facilitate screening novel interventions to understand how they affect particular electrophysiological patterns, and what clinical population might have a deficit in particular patterns.  The ultimate goal is that the resulting work be highly relevant to the development of pharmacological, electrical, magnetic, or other types of interventions that can enhance cognition sufficiently to improve real-life functioning for patients.

Institute Interests

All applicants are encouraged to contact Scientific/Research staffat NIMH or NINDS before submitting a grant application.

NIMH Interests

Applications of interest to the National Institute of Mental Health (NIMH) include hypothesis-driven projects focused on neuropsychiatric disorders that include cognitive impairments.  These disorders include autism spectrum disorders, including single-gene disorders such as Fragile X syndrome and accompanying intellectual disability; schizophrenia spectrum disorders; and mood and anxiety disorders.  The NIMH Strategic Plan lays out the Institute priorities, which applicants are strongly encouraged to review when preparing an application (http://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml). 

NIMH will consider support for only those applications that study cognition using quantitatively-defined behavioral measures as outcomes.  Grant applications should use active interventions to test mechanisms of circuit functions.  Descriptive and correlational studies without empirical tests of causality will be of very low priority for NIMH.

Translating discoveries into evidence-based treatments is predicated on testing candidate therapeutics using fundamental model systems in vitro and in vivo. The value of such research is greatly enhanced when detailed information is made available about study design, execution, analysis and interpretation.  Please also see NOT-MH-14-004, "Enhancing the Reliability of NIMH-Supported Research through Rigorous Study Design and Reporting".

NINDS Interests

Applications of interest to the National Institute of Neurological Disorders and Stroke (NINDS) include hypothesis-driven projects focused on neurological disorders that feature cognitive impairments.  These disorders can include, but are not limited to the epilepsies and other intellectual and developmental disabilities (IDD) such as tuberous sclerosis complex, Rett Syndrome, Fragile X Syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, and Down Syndrome, along with other disorders known to exhibit imbalances in excitatory/inhibitory neurotransmission which are likely to alter systems level electrophysiology patterns.  In these neurodevelopmental disorders, understanding how perturbations of molecular events at the cellular level translate to altered circuit-level functions and network dynamics may be key to developing therapeutics that improve the disabling cognitive features of the disorder.

In this FOA, NINDS encourages applications to test hypotheses that would illuminate the basic mechanistic relationships underlying cognitive co-morbidities in the epilepsies and neurodevelopmental disorders.  Studies to assess the predictive value of model animals or non-invasive human testing in developing treatments to improve or prevent cognitive dysfunction in people with epilepsy or neurodevelopmental disorders are also encouraged. 

Applicants should note that NINDS will consider support for only those applications that study cognition using quantitatively-defined behavioral measures as outcomes.  Applications should use approaches designed to determine the mechanisms of circuit functions.  Model-based strategies are strongly encouraged; descriptive and correlational studies without empirical tests of causality will be of very low priority to NINDS.  In addition, NINDS has published guidelines to enhance transparency in reporting and promoting scientific rigor in NINDS-funded studies (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html; http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf). Applicants are strongly encouraged to review these guidelines when preparing an application.

Section II. Award Information
Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New
Resubmission
Revisions

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

The combined budget for direct costs for the two year project period may not exceed $275,000. No more than $200,000 may be requested in any single year. Applicants may request direct costs in $25,000 modules, up to the total direct costs limitation of $275,000 for the combined two-year award period.

Award Project Period

The project period is limited to 2 years.  

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information


1. Eligible Applicants


Eligible Organizations

Higher Education Institutions

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility


Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

Section IV. Application and Submission Information


1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.  

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.  

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed.  

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed. 

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.  

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy: Every application should address at least one of the four topic areas listed in Section I, “Funding Opportunity Description.” 

In addition, all applications under this FOA are also expected to describe how the application fulfills the following requirements as part of the Approach section of the Research Plan:

As part of the Significance section, all projects should provide a strong scientific rationale for the specific biological intervention chosen (pharmacological or otherwise), in particular whether the intervention can be expected to selectively alter a specific aspect of a systems-level temporal dynamic pattern in a particular direction.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix:  Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide. 

PHS 398 Cumulative Inclusion Enrollment Report

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide. 

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How well does the project fulfill each of the following questions:

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?   

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?   

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Are behavioral measures defined quantitatively?

Does the project include in vivo manipulations that are not only behavioral interventions, and can they be expected to selectively alter an electrophysiological parameter in a particular direction? 

If theoretical computational work is proposed, does it reciprocally and iteratively interact closely with experimental work?  Does the experimental work include active manipulations?  Will it test systems-level computational algorithms that underlie cognition, such as modeling how increasing the amplitude of theta oscillations in one brain region affects oscillations in various frequency bands in other brain areas during spatial working memory?

If EEG work is proposed, does it include spectral analyses, and not rely on event-related potentials (ERPs)?

Does the project employ recording methods that detect neural activity directly, without relying on blood flow measures, and which have the appropriate temporal resolution?   

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?  

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?   

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children 

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center of Scientific Review, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information


1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.      

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement. 

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html

TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

Bettina D. Osborn, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-1576
Email: osbornb@mail.nih.gov

Brandy Fureman, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1917
Email: furemanb@ninds.nih.gov

Peer Review Contact(s)

Christine Melchior, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1713
Email: melchioc@csr.nih.gov

Financial/Grants Management Contact(s)

Terri Jarosik
National Institute of Mental Health (NIMH)
Telephone: 301-443-3858
Email: tjarosik@mail.nih.gov

Tijuanna E. DeCoster, MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices



NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy
NIH... Turning Discovery Into Health®



Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.