Part 1. Overview Information

Key Dates

All applications are due 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.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of 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. Notice of Funding Opportunity Description

Background

Disorders of complex brain function such as schizophrenia, bipolar disorder, major depression, anxiety disorders, tic disorders and autism exact a very high toll in care and lost productivity in the United States. However, progress in understanding the causes and developing effective treatments has been slow, in part because these brain disorders currently do not have well-defined biological signatures of pathology that could be utilized in experimental neuroscience paradigms or targeted for intervention. Recently, there has been substantial progress in identifying statistically significant common and rare disease-associated genetic variants that confer risk for mental illnesses. In parallel, there are now a wide array of novel technologies available to probe brain biology at high resolution and sensitivity and across different molecular, cellular, and circuit scales. This progress provides leverage for neuroscientists to identify cellular, molecular, and circuit processes that may be differentially affected in these disorders. Although the questions posed may not be mature from the perspective of hypothesis testing for disease relevance, nurturing the initial stages of discovery and hypothesis generation is critical for advancing our understanding of the factors that contribute to disorders of complex brain functions.

To gain a broader understanding of complex brain disorders, it is important to understand the biology of the multiple factors associated with disease risk and the context in which they act at a molecular, cellular and circuit level. For example, filling knowledge gaps in gene ontology (i.e., molecular functions, cell type selectivity and biological processes and relationships) will benefit the study of genetic contributions to disease by increasing the accuracy and reliability of gene and protein network analyses for tissue and cell-specific processes. Such studies will ultimately facilitate the identification of biological processes / pathways affected by disease risk and targets of therapeutic intervention.

Relevant measures at these biological scales can include intracellular signaling mediated by second messengers, neuromodulators, neurotrophins and ion channels downstream of receptors; protein synthesis, modification, trafficking and degradation; membrane and organelle dynamics; bioenergetics; metabolic mechanisms; alterations in cell architecture, polarity and/or synaptic connectivity; synaptic transmission and regulation of the co-release of multiple transmitters from individual neurons, mechanisms of bidirectional signaling between neurons, glia and epithelial cells; homeostatic scaling; gut-brain interactions; changes that target sensitive periods of developmental plasticity or perturbations in circuit dynamics such as excitatory/inhibitory balance and oscillatory activity.

Research Objectives

This NOFO encourages research on the biology of high confidence risk factors associated with complex brain disorders, with a focus on the intracellular, transcellular and circuit substrates of neural function. For the purposes of this NOFO, the term “complex” can refer to a multifactorial contribution to risk (e.g., polygenic and/or environmental) and/or highly distributed functional features of the brain disorder. Studies may be either hypothesis-generating (unbiased discovery) or hypothesis-testing in design and may utilize in vivo, in situ or in vitro experimental paradigms, e.g., model organisms or human cell-based assays. While behavioral paradigms and outcome measures can be incorporated into the research design to facilitate the characterization of intracellular, transcellular and circuit mechanisms, these are neither required nor expected. Studies should not attempt to “model” disorders but instead should aim to elucidate the neurobiological impact of individual or combined risk factor(s), such as the affected molecular and cellular components and their relationships within defined biological process(es). This can include the fundamental biology of these factors, components and processes. The resulting paradigms, component pathways and biological processes should be disseminated with sufficient detail to enrich common and/or federated data resources (e.g., those contributing to the Gene Ontology, Synaptic Gene Ontology, FAIR Data Informatics) in order to bridge the gap between disease risk factors, biological mechanism and therapeutic target identification. See Section IV, Application and Submission Information,   Resource Sharing Plan.

Applicants are strongly encouraged to take advantage of novel technologies (e.g., from the BRAIN Initiative) and other resources (e.g., genetically modified organism repositories, human cell lines from the NIMH Repository and Genomics Resource) that will facilitate the consideration of genetic background / strain differences, sex as a biological variable, sample size and other aspects of experimental/statistical rigor.

Examples of relevant research include, but are not limited to:

• Analysis of gene(s) where variants have been associated with disease risk at genome-wide significance, but where the basic biology of those genes is poorly understood (e.g., where functional analysis would enrich gene ontology). Applicants are encouraged to incorporate state of the art methods for testing the functional effects of genes and gene variants (e.g., CRISPR/Cas9-mediated editing or newly emerging temporal / spatial control technologies).
• Investigations of mechanisms by which high confidence environmental risk factors influence molecular, cellular or circuit-level processes, alone or by interaction with genetic risk factors.
• Incorporation of the developmental trajectory of biological processes into experimental designs, including designs that identify developmentally critical / sensitive periods to environmental influence.
• Optimization and implementation of novel cell-based experimental systems such as induced pluripotent stem (iPS) cells, including those that are derived from human patients or engineered to carry disease-associated genetic variants, in order to characterize disease-relevant mechanisms. Applicants are encouraged to request access to the NIMH Repository and Genomics Resource List of Studies or iPS cell collection to determine if source cells for reprogramming or existing iPS cell lines are already available. Applicants proposing to derive new iPS cell lines should refer to instructions in Section IV. Application and Submission Information, Resource Sharing Plan.
• Development/optimization of new biological tools or scalable technologies for reporting or manipulating the activity levels and neurobiological functions of brain signaling / effector molecules relevant to complex brain disorders.
• Inclusion of computational approaches, which may include mapping of experimentally produced data to existing reference data to inform biological or pathophysiological relevance of results.

Non-responsive topics

The following research topics are not responsive to this NOFO and will be withdrawn prior to review:

• Development or use of a ‘model of’ a disease (e.g., based on purported face validity and interpretation of behaviors as symptoms);
• Research premised on ‘candidate’ risk genes that are not identified by well-powered, statistically significant genome-wide association;
• Research premised on ‘candidate’ environmental risk factors that are not based on well-powered, statistically significant epidemiological data;
• A primary focus on phenotyping human subjects or clinical populations, which is more appropriate for other NOFOs (except for those with a strong focus on cell or tissue-based assays, including generation and/or characterization of iPS cells, which is appropriate for this NOFO);
• A primary or sole focus on behavioral paradigms/measures, pharmacology or drug discovery, and/or immunological challenge paradigms, which are more appropriate for other NOFOs.

Applicants are strongly advised to consult with NIMH institute staff early when developing their projects to ascertain that their proposed study is aligned with the NOFO purpose. Applicants are also strongly encouraged to align projects according to (1) the NIMH Strategic Plan, along with NIMH guidance on (2) the use of model organisms for disease-relevant research and (3) biological investigations of genes associated with disease risk. The following links provide relevant information:

• Funding Strategy for Research Grants
• A Hypothesis-Based Approach: The Use of Animals in Mental Health Research
• NOT-MH-19-053: Notice of NIMHs Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Pre-clinical Studies (nih.gov)
• NOT-MH-22-010: NIMH Priorities on Research Using Genetically Modified Nonhuman Primates. (nih.gov)
• Guidance for Applicants Following the Report of the National Advisory Mental Health Council Workgroup on Genomics

The present NOFO (R21 activity code) can be used for applications to develop early stage, high-risk, exploratory or proof-of-concept approaches where there is little or no preliminary data. Applicants proposing to develop lines of inquiry where feasibility or proof of concept has been established should apply to the companion R01 NOFO (PAR-24-024  ).

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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)

Local 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)

Federal Governments

• 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
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) – 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. 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 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.

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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 NOFO 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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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.

Page Limitations

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

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

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.

R&R Subaward 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:

The primary focus of applications responding to this announcement is on the biology of high confidence risk factors associated with complex brain disorders, with a focus on the intracellular, transcellular and circuit substrates of neural function. For the purposes of this NOFO, the term “complex” can refer to a multifactorial contribution to risk (e.g., polygenic and/or environmental) and/or highly distributed functional features of the brain disorder. Studies may be either hypothesis-generating (unbiased discovery) or hypothesis-testing in design and may utilize in vivo, in situ or in vitro experimental paradigms, e.g., model organisms or human cell-based assays. While behavioral paradigms and outcome measures can be incorporated into the research design to facilitate the characterization of intracellular, transcellular and circuit mechanisms, these are neither required nor expected. Studies should not attempt to “model” disorders but instead should aim to elucidate the neurobiological impact of individual or combined risk factor(s), such as the affected molecular and cellular components and their relationships within defined biological process(es). This can include the fundamental biology of these factors, components and processes.

The Research Strategy should:

• Define the current state of the science as a benchmark against which the new study will be developed and executed;
• Provide a clear rationalization for studying any risk factors, with a focus only on those supported by rigorous, unbiased, sufficiently powered studies (e.g., genome-wide association or environmental risk epidemiology);
• Develop or exploit novel tools, technologies, resources and reference datasets (e.g., those developed by the BRAIN Initiative, found in the NIMH Repository and Genomics Resource or in clinical or genomic data archives) to improve the sophistication, robustness or reproducibility of the design. As an alternative, describe any proposed unique conceptualization of analytic approaches being applied to the study;
• Address the contribution of genetic background (e.g., human donor diversity, mouse strain differences) where appropriate to the questions being asked, in order to account for modifiers of the risk factor(s);
• If proposing a discovery-based, hypothesis-generating approach, focus on designs that will generate unambiguous, highly interpretable data used to generate new hypotheses and broadly advance the field at large;
• Define key aspects of experimental rigor (as appropriate) and how they will be addressed in the study, including but not limited to:
  • Issues of statistical, computational and/or experimental robustness and reproducibility;
  • Primary and secondary statistical and/or experimental outcomes to be assessed (e.g., gene fold change, variance explained) and clearly state how these relate to proposed objectives;
  • Number of experimental and control groups;
  • The 'experimental unit' in the analysis and the implications thereof (e.g., there is a difference between N samples from one cell line, as distinct from one sample from each of N cell lines, or combining samples from multiple lines);
  • The number of 'experimental units' in each experimental group;
  • The total number of 'experimental units' to be measured;
  • The number of times each 'experimental unit' will be measured;
  • The number of independent replications of each experiment;
  • Steps taken to minimize the effects of bias (e.g., batch effects, blinding, randomization) or an explanation of why this would not be appropriate;
  • Calculated effect sizes and justification regarding how they are biologically relevant;
  • Demonstration that statistical power calculations are grounded in justifiable and explicit assumptions about both anticipated effect size and variability of the experimental effects;
  • If statistical power calculations cannot reasonably be applied, provide an alternative rationale for the choice of numbers (explanations based solely in terms of 'usual practice' or with reference solely to previously published data will not be considered adequate).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

 Applicants are expected to register resources supported by this NOFO in FAIR Data Informatics (https://scicrunch.org/) and use Research Resource Identifiers (RRID) assigned by (https://scicrunch.org/resources) in any publication supported by this NOFO.

NOT-MH-21-265 outlines the expectation that investigators who propose to generate human subject-derived reprogrammed cells in their NIMH-funded research will ensure that both the source biospecimen cells and reprogrammed derivatives (e.g., iPS cells) are made available to the research community through the NIMH Repository and Genomics Resource. Investigators are expected to discuss plans with Program staff early in the planning stage and prior to submitting an application. Depending on the details of the plan, Program staff may recommend that applicants propose and budget in their application for iPSC derivation to be done as a fee-for-service by the core facility associated with the NIMH Repository. Sharing plans consistent with this policy will be finalized prior to the release of, and specified in, the Notice of Award.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

The plan should describe how resulting paradigms, component pathways and biological processes will be disseminated with sufficient detail to enrich common and/or federated data resources. Examples include those contributing to Gene Ontology (http://geneontology.org/docs/contributing-to-go/) or Synaptic Gene Ontology (https://syngoportal.org/submit.html).

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded under this Notice of Funding Opportunity (NOFO) are expected to share those data via the National Institute of Mental Health Data Archive (NDA; see NOT-MH-23-100). Established by the NIH, NDA is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NOT-MH-23-100 outlines the expectation that researchers who are funded by NIMH for human subject recruitment studies will deposit all raw and analyzed data (including, but not limited to, clinical, genomic, imaging, and phenotypic data) from experiments involving human subjects into the NIMH Data Archive (NDA). Applicants should review NOT-MH-23-100 for additional information when preparing their sharing plan. NDA links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this NOFO are expected to use these technologies to submit data to NDA.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant, and b) a budget strategy that will cover the costs of data submission. The NDA website provides two tools to help investigators develop appropriate strategies: 1) the NDA Data Submission Cost Model which offers a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent available from the NDA's Data Contribution page. Investigators are expected to certify the quality of all data generated by grants funded under this NOFO prior to submission to NDA and review their data for accuracy after submission. Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication, or prior to the end of the grant, whichever occurs first (see NDA Sharing Regimen for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied. For more guidance on submitting data to NDA, refer to the NDA Data Sharing Plan on the NDA website. NDA staff will work with investigators to help them submit data types not yet defined in the NDA Data Dictionary.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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 and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

NIMH expects investigators for this funding announcement to collect Common Data Elements (CDEs) for mental health human subjects research. Unless NIMH stipulates otherwise during the negotiation of the terms and conditions of a grant award, this Notice applies to all grant applications involving human research participants. The necessary funds for collecting and submitting these CDE data from all research participants to the NIMH Data Archive (NDA) should be included in the requested budget. A cost estimator (https://nda.nih.gov/ndarpublicweb/Documents/NDA_Data_Submission_Costs.xlsx) is available to facilitate the calculation of these costs. NIMH may seek further information regarding CDEs prior to award. Additional information about CDEs can be found at the NIMH webpage on Data Sharing for Applicants and Awardees.

6. 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.

7. 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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier 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 and compliance with application instructions by the Center for Scientific Review and responsiveness by NIMH  , NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission 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 emphasize 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.

The primary focus of applications responding to this announcement is on the biology of high confidence risk factors associated with complex brain disorders, with a focus on the intracellular, transcellular and circuit substrates of neural function. For the purposes of this NOFO, the term “complex” can refer to a multifactorial contribution to risk (e.g., polygenic and/or environmental) and/or highly distributed functional features of the brain disorder. Studies may be either hypothesis-generating (unbiased discovery) or hypothesis-testing in design and may utilize in vivo, in situ or in vitro experimental paradigms, e.g., model organisms or human cell-based assays. While behavioral paradigms and outcome measures can be incorporated into the research design to facilitate the characterization of intracellular, transcellular and circuit mechanisms, these are neither required nor expected. Studies should not attempt to “model” disorders but instead should aim to elucidate the neurobiological impact of individual or combined risk factor(s), such as the affected molecular and cellular components and their relationships within defined biological process(es). This can include the fundamental biology of these factors, components and processes.

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).

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.

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.

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.

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 for 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 will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

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. 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:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.”

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, 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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 the threshold.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

David Panchision, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-402-3969
Email: panchisiond@mail.nih.gov

Gagan Pandya, Ph.D.
Center for Scientific Review
Telephone: 301-435-1167
Email: pandyaga@mail.nih.gov

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: weissh@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.

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 Part 75 and 2 CFR Part 200.