PAR-14-158: Temporal Dynamics of Neurophysiological Patterns as Potential Targets for Treating Cognitive Deficits in Brain Disorders (R21)

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	August 31, 2017 - This PAR has been reissued as PAR-17-463. May 10, 2017 - New NIH "FORMS-E" Grant Application Forms and Instructions Coming for Due Dates On or After January 25, 2018. See NOT-OD-17-062. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) NOT-OD-16-011 - Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications (November 18, 2015) 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.

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:

An example of Topic 1 would be to conduct electrophysiological recordings in a model organism relevant to neuropsychiatric disease during a spatial working memory task. The goal would be to examine whether theta precession, phase-amplitude coupling, or other neural patterns are aberrant, and what systems-level aspects of the electrophysiological patterns could be modified to improve task behavior. For example, would particular patterns of electrical stimulation improve theta precession, and would this improve spatial as well as non-spatial relational processing? What is the mechanism by which the changed neural pattern improves behavior? Methods for altering neural patterns could include pharmacological intervention, optogenetic methods, patterned electrical stimulation, or other methods, as long as the method allows for understanding what variables of the temporal dynamics are the drivers of behavioral improvements, such as increases or decreases in the amplitudes of particular oscillatory frequencies, the co-modulation of particular frequencies, or other characteristics of temporal patterns and spike timing.
Another example of Topic 1 would be to use patterned brain stimulation to test whether relational processing could be improved in non-spatial, but serial, tasks such as transitive inference. For example, could sharp wave ripples be triggered to occur artificially, and might this improve cognition? Can the fidelity of replay be improved? Work of this type would be especially encouraged in nonhuman primates because of more relevant brain anatomy and the possibility for more complex behavioral tasks.
An example of Topic 2 would be to determine how over-activation of metabotropic glutamate signaling, or GABA receptor dysfunction in FMR1 knockout animals leads to particular changes in neural patterns and cognition, and whether any interventions (pharmacological or otherwise) can correct the systems-level neural coordination during behavior.
An example of Topic 3 would be to test whether changes in neural coordination patterns in rodent models of relevant phenotypes predict similar intervention-induced changes in patients' EEG signals, during an equivalent behavioral task. The interventions in patients could be noninvasive brain stimulation (e.g., patterned transcranial magnetic stimulation or transcranial direct current stimulation) or medications. This type of work should also test whether the cognitive/behavioral improvements seen in rodents also predict improvements in patients.
An example of Topic 4 would be to develop a biologically-realistic, computational model for predicting effects of noninvasive brain stimulation on particular frequencies of cortical and subcortical oscillations and how they interact across trial time and across brain areas. Another example might be to model and then experimentally test the effects of interneuron signaling on systems-level temporal dynamics.

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:

All projects should employ active manipulations in awake, behaving vertebrate animals. The manipulations can consist of electrical or magnetic brain stimulation, optogenetics, genome editing, pharmacological compounds including existing or novel medications, or other modalities, but they cannot consist solely of behavioral manipulations. Biological manipulations can be tested in conjunction with behavioral training, such as brain stimulation protocols to augment the effectiveness of applied behavioral analysis therapy in autism. In general, novel interventions are encouraged.
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 well-defined aspect of a systems-level temporal pattern in a particular direction (e.g., increasing the power of a specific oscillatory frequency).
All projects are expected to include in vivo, neurophysiological systems-level measures during behavior in each species. Computational/analytic work in particular is expected to reciprocally and iteratively interact closely with experimental work. The use of any non-mammalian species must be clearly justified, providing strong evidence that electrophysiological patterns during cognition are likely to generalize from animals to humans.
EEG work is expected to include spectral analyses; event-related potentials (ERPs) provide insufficient mechanistic detail for the present set of goals.
All projects are expected to employ recording methods that detect neural activity directly, without relying on blood flow measures. All recording methods are expected to have the appropriate temporal resolution to address temporal dynamics of coordinated neural activity during cognition.

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 (https://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

Public/State Controlled Institutions of Higher Education
Private Institutions of Higher Education

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

Hispanic-serving Institutions
Historically Black Colleges and Universities (HBCUs)
Tribally Controlled Colleges and Universities (TCCUs)
Alaska Native and Native Hawaiian Serving Institutions
Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

Small Businesses
For-Profit Organizations (Other than Small Businesses)

Governments

State Governments
County Governments
City or Township Governments
Special District Governments
Indian/Native American Tribal Governments (Federally Recognized)
Indian/Native American Tribal Governments (Other than Federally Recognized)
Eligible Agencies of the Federal Government
U.S. Territory or Possession

Other

Independent School Districts
Public Housing Authorities/Indian Housing Authorities
Native American Tribal Organizations (other than Federally recognized tribal governments)
Faith-based or Community-based Organizations
Regional Organizations

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.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

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