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 SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from 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.

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. 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

Background and Research Objectives

Despite large investments by pharmaceutical and biotech industries, the last 20 years have yielded few novel treatments to address unmet needs of individuals suffering with mental illnesses. Multiple factors have contributed to the low success rate, including insufficient understanding of disease pathophysiology and the basis for heterogeneity in presentation and treatment response of patients within categorical diagnoses. The NIMH supports efforts such as the Research Domains Criteria (RDoC) project to transform diagnostics by promoting research that extends beyond the current symptom-based diagnostic categories (i.e., Diagnostic and Statistical Manual, DSM) to identify functional domains whose disruption contributes significantly to disability across diagnoses. However, RDoC was designed to provide a context to examine functional domains and relevant neurobiology in humans, not in animals. While clinical neuroscience advances our understanding of circuit disruptions driving behavioral deficits in humans, the need for comparable efforts in basic neuroscience has become evident, particularly across the therapeutic development pipeline where behavioral screens in animals often contribute to the selection of lead candidates for the development of novel treatments for mental illnesses. The goal of this FOA is to address this gap by supporting the initial development and testing of innovative neurophysiological and behavioral measures that have the potential to serve as translational screening assays in preclinical species.

The poor predictive value of current preclinical screening model systems in therapeutic development for neurological and mental disorders is well recognized by the pharmaceutical industry and was the topic of a high profile workshop (see National Academies of Sciences, Engineering and Medicine report, Therapeutic Development in the Absence of Predictive Animal Models of Nervous System Disorders: Proceedings of a Workshop). Commonly used batteries of behavioral assays in rodents such as the forced swim test, tail suspension test, elevated plus maze, novelty induced suppression of feeding, sucrose preference, open field activity test, and reversal of drug-induced hyperlocomotion or grooming are useful in some contexts, such as addressing effects of novel ligands on brain penetrance and dose response. However, these measures do not reflect specific neural processes or predict efficacy. Relationships between these measures in animals and behavioral deficits or neural activity irregularities in patients is unknown.

Technical advances in neuroscience, including those generated through the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, now provide tremendous opportunities to understand the functional impact of cell and circuit diversity and identify novel therapeutic targets. Still, while the neurobiology underlying target identification has advanced, neuroscience-based approaches to screen potential targets and treatment candidates in the therapeutic development pipeline have not kept pace. The current FOA is built on the premise that it is possible to develop neurophysiological and behavioral measures in animals that mirror a subset of brain activities and functional domains suggested by clinical neuroscience to impact mental health and disability, here defined as potentially “clinically relevant”. To advance such measures as assays for treatment development, this FOA encourages applications aimed at addressing three specific goals; 1) identification and optimization of measures that reflect clinically relevant brain processes that are potentially conserved between preclinical species and humans, 2) evaluation of the sensitivity and selectivity of the potential measures as screening assays by examining their performance in response to perturbations such as drugs, and 3) testing the role of the brain pathways hypothesized to underlie the physiological and/or behavioral assay measure. Completion of these goals is expected to unveil novel, research-based physiological and/or behavioral assays that are poised for cross validation against results of similar measures in humans and then potential use as preclinical assay measures in a treatment development pipeline for mental illnesses. Thus, while human testing is not a component of this FOA, the measures to be developed in animals through this FOA should be designed so the coherence, or lack of concurrence, of the assay performance across species to humans can be assessed in future projects. In this way, assays developed here may be considered the preclinical prequel to subsequent projects aimed at evaluating the assays for coherence of performance between the preclinical species and healthy humans.

Research Scope

The FOA supports the initial stages in the development, optimization, and evaluation of novel in vivo measures as potential assays in early (pre-first in human) screening of therapeutic candidates. Assays may include neurophysiological measures and may include behavioral measures. Key considerations are listed below but at a minimum, measures should be amenable to study in live animals and in future studies in humans, and they must be innovative.

Priority will be given to applications that include all three of the following phases:

1. Optimization, in animals, of novel, predominantly non-invasive neurophysiological or behavioral measures reflecting activity of clinically relevant brain processes or functional domains that are disrupted within or across mental illnesses. Optimization should focus on mirroring testing parameters or measures used in human experiments where human assays exist or developing tests that have potential value for future translation to humans.
2. Evaluation of the performance of the physiological or behavioral measures using FDA-approved drugs or other interventions with demonstrated effects on the targets, in a dose ranging study that includes pharmacokinetic/pharmacodynamic (PK/PD) readouts.
3. Mechanistic testing of brain processes and/or circuits proposed as key drivers of the neurophysiological or behavioral assay measures. For example, a study might include optogenetic or chemogenetic approaches to manipulate specific circuits in combination with in vivo electrophysiological measures to verify circuits contributing to specific EEG power spectral changes elicited by a cognitive challenge. Studies are expected to include a subset of studies that address the relationship between brain activity measures and changes in the physiological or behavioral assay measures in response to the same drugs or perturbations evaluated in the assay optimization stage.

This FOA aims to stimulate the development of in vivo assays to address translational gaps in treatment development for mental illnesses. Support will be provided for assay development efforts in animals that propose quantitative measures of neurophysiological and/or behavioral processes where there is reasonable evidence to suggest that measure is a potential contributor to functional deficits of individuals with mental illnesses (e.g., cognitive function, impulsivity, motivation, etc.).

Examples of relevant neurophysiological and/or behavioral measures for development and evaluation as assays include, but are not limited to:

• Spectral EEG or MEG to assess brain rhythms within different frequencies.
• Measures that tap into fundamental processes that are disrupted within or across mental illnesses such as aspects of vigilance, attention, neurophysiological measures of neural plasticity, or affect regulation.
• Measures relevant to anhedonia that can be assessed in animals and humans such as reward learning, cognitive effort during learning, measures of wanting versus liking, etc.
• Measures relevant to impulsivity such as delay discounting, behavioral inhibition.
• Measures that tap into neural circuit activity linked to specific cognitive domains. For example, the CNTRICS program identified constructs across six cognitive systems relevant to schizophrenia and selected tasks from cognitive neuroscience that measure the constructs and the CNTRACS initiative extended those measures (goal maintenance, relational encoding, gain control, visual integration).
• Prefrontal cortical top-down inhibitory control over subcortical and brainstem systems that regulate autonomic function (brain noradrenergic hyperfunction, electrodermal response, pupillometry).
• Measures of sleep physiology (sleep spindle characteristics, sleep microstructure) relevant to mood and cognitive function. Note that studies of circadian rhythmicity mechanisms per se are not appropriate for this FOA.
• Measures in awake behaving animals relevant to human functional or molecular imaging (fMRI or MRS).
• Additional innovative measures are encouraged including the use of novel tools or methods arising from the BRAIN Initiative .
• Computational approaches connecting behaviors with circuit functions are encouraged. NIMH is particularly interested in new computational theories of complex behaviors able to link multiple behavioral (and circuit) parameters, tracked over time to make predictions on potentially back-translatable (animal-to-humans) behavioral outcomes.

Mechanistic testing of underlying brain pathways will be tailored to the proposed assay measure. For example, studies might examine whether specific changes in dopamine signaling to striatum or prefrontal cortex reliably predict speed or accuracy of reward contingency learning. These studies are critical for advancing a new generation of in vivo assays for therapeutic development that are grounded in a clinically-meaningful neurobiological context.

The main emphasis must be on developing novel, clinically relevant measures as assays. While the neurophysiological or behavioral measures may not be innovative by themselves, their inclusion in a therapeutic development pipeline must be novel.

Since this work is expected to identify and optimize novel assay measures that can subsequently be compared with measures in healthy humans, proposed neurophysiological and behavioral assay measures should have analogs that can be performed in healthy humans.

While neurophysiological measures such as event-related potential (ERP) may be useful for refining critical temporal parameters of an assay, they have insufficient specificity to assess effects across trials. Studies proposing EEG measures as assays should focus on frequency band measures for this FOA.

Measures should be innovative in relation to published relevant literature. For example, assays of plasticity mechanisms could focus on novel neurophysiological measures. Many behavioral readouts of learning and memory are well established and already sufficiently represented in the NIMH portfolio, particularly for contextual versus cued fear learning.

Applications Not Responsive to this FOA

The following will be considered not responsive and will not be reviewed:

• Studies involving human subjects.
• Development or inclusion of animal models "of" mental disorders. Projects should adhere to the recommendations in NOT-MH-19-053 Notice of NIMH’s Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Pre-clinical Studies, as well as the Recommendations of the NAMHC Workgroup on Genomics.
• Broad batteries of behavioral tests or clinical battery testing.
• Behavioral assays without inclusion of measures of associated brain processes and/or neural circuits.
• Studies aimed solely at developing measures of circadian rhythmicity or clock regulatory mechanisms as assays.
• Cell culture or in vitro assay measures.
• Hypothesis testing beyond evaluation of the relationship of the neurophysiological or behavioral measures to specific circuits. For example, studies focused primarily on testing brain systems underlying functional domains, pathophysiology of disease, or treatment response are not appropriate.
• Studies aimed primarily at evaluating novel therapeutic targets or treatment candidates.

Milestones

All projects must propose a timeline for completion of the required components of assay development, including (1) assay measure optimization, (2) evaluation of assay performance, and (3) mechanistic testing. If more than one measure is proposed for optimization, the timeline must include plans for optimization of each measure. An additional milestone should outline plans and a timeline for dissemination of results, regardless of outcome.

Potential applicants are strongly encouraged to read the Frequently Asked Questions (FAQs) for this FOA and to contact NIMH Scientific/Research Contacts(s) prior to preparing an application.

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 FOA.

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 Government

• 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 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.

• 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 registration; 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 his/her 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 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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 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 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 FOA. 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 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.

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 FOA.

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.

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

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

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.

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

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

Specific Aims: Provide the overall goals for the entire application. The Specific Aims section should include distinct Aims for each of the three phases (assay optimization, performance evaluation, and mechanistic testing).

Research Strategy: Organize the Research Strategy in the subsections identified below.

Applicants should describe the three phases within these subsections as described, including milestones for each phase.

Significance:

• Discuss how the proposed measure(s) of neurophysiological or behavioral processes address a translational gap including how they relate to brain activities and functional domains suggested by clinical neuroscience to impact mental health and disability.
• Detail how do the proposed measures relate to currently available measures used to assess functional domains in humans.
• Describe how the results will add value to a therapeutic development pipeline regardless of outcome.

Innovation:

• Explain how the project offers a novel approach to evaluating potential new treatments for mental illnesses.
• If similar types of measures are already in common practice in a preclinical treatment development pathway, explain why the proposed approach would be expected to provide important new information or a benefit over existing measures.

Approach: This section should cover the application as a whole as well as the three phases with the appropriate headers within the text.

Overall Approach:

• Justify the choice of measure(s), including a brief description of evidence that the measures have potential to either directly or indirectly assess activity or function within the same targeted circuits or physiological processes in both the preclinical species and humans.
• Explain the rationale behind the choice of preclinical species, assays, and endpoints for all studies.
• Provide evidence of feasibility to perform the measurements and manipulations in both preclinical species and humans (the latter in future studies).
• Include discussion of evidence indicating how the planned measures/manipulations are relevant to key neural circuits/processes that are disrupted in mental disorders and with potential clinical benefit if corrected.
• Describe the research team's approach toward selecting, optimizing and evaluating the assays.
• Describe goals for each of the three phases:
  • For phase 1, optimization: clearly describe studies aimed at measure optimization to approximate measures that are, or could be, performed in humans. Include strategies for addressing barriers that may arise in the course of optimization to facilitate future head to head comparisons with comparable measures in humans. For example, if the goal is to advance task driven EEG measures in rodents, describe studies aimed at improving signal to noise or determining optimum electrode placement.
  • For phase 2, performance evaluation: detail how performance of the physiological or behavioral measure(s) will be evaluated as potential assay(s) using FDA approved drug(s) or other intervention with demonstrated actions on the CNS target, in a dose ranging PK/PD study. Describe the rationale for the study design, including dose range, PK sampling, route, and timing of the drug in relation to testing. For example, detail if dose selection is based on brain target occupancy, how measurements are timed for known Cmax, etc.
  • For phase 3, mechanistic testing: detail methods to be used to test the involvement of hypothesized circuits, including procedures for both directly modifying the circuits and recording effects on circuit activity during simultaneous measurement of the physiological or behavioral measure. For example, a study might include optogenetic or chemogenetic approaches to manipulate specific circuits in combination with in vivo electrophysiological measures to verify circuits contributing to specific EEG power spectral changes elicited by a cognitive challenge.
• Applications must also include a subset of experiments evaluating the relationship between brain activity changes and physiological/behavioral assay measures in response to the same intervention evaluated in the performance evaluation stage.
• Applications are strongly advised to provide alternate strategies should results suggest the tested circuit is not critical for the measure.
• Include enough details to allow reviewers to evaluate the rigor of the experimental design. Describe the study design in detail, including the strain, age, and sex of animals, power analyses and associated assumptions for the determination of sample size, statistical handling of the data, procedures used for addressing sex as a biological variable, blinding and randomization.
• Describe plans for data analysis and interpretation including the PK/PD relationship and what would constitute a go/no-go decision for further measure development, including later tests for cross-species conservation of the measure, and implementation in a therapeutic discovery pipeline.
• Include a detailed Results and Interpretation section that outlines how results will be evaluated and a timeline for dissemination of results to the broader research community.

Milestones:

Specific goals and feasibility milestones must be clear and linked to the timeline for completing the studies in no more than 5 years. Separate milestones should be proposed for each of the 3 study components for assay optimization and testing. The milestones should be quantifiable and scientifically justified. If more than one measure is proposed, separate milestones should be provided for each. Required milestones are expected to address assay measure optimization (1), evaluation of assay performance (2), and mechanistic testing (3). An additional milestone should outline plans and a timeline for dissemination of results, regardless of outcome.

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. 

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.

While it is understood that many of the approaches and early data generated through this FOA will be at an early proof-of-concept stage, a central goal is to contribute a toolset that facilitates the adoption of robust, experimentally based measures in the early phases of a therapeutic development pipeline for mental illnesses. Regardless of study outcomes or publication status, the experimental protocols and data generated through this FOA will be valuable to the research community by indicating assay measures with ambiguous relationships to brain circuits as well as those poised for assessment of potential predictive value in future cross species comparisons.

Accordingly, all applications are expected to include a detailed Data and Experimental Protocol sharing plan that specifies how data will be shared and who will be responsible for managing sharing of all protocols and data, consistent with achieving the goals of this program.

Applicants must include the following key elements:

• Description of how protocols and data will be shared as well as schedule/timeline for sharing data.
• Detailed plans on how data will be made broadly available.

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.

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.

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

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 Policy on Late Application Submission.

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.

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.

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 fieldof 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 FOA 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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

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.

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

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? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Specific to this FOA:

Is there a reasonable likelihood that completion of the research objectives could lead to a novel assay that allows for more biologically linked prediction of effects of novel therapeutic treatment candidates from preclinical species to humans? Does the assay measure assess a brain process of relevance to mental illnesses (i.e., is there a reasonable chance that the assay measure could show a difference in patients with mental illnesses)?

How strong is the rationale provided to support the choice of manipulation for evaluating the performance of the assay measure?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

Specific to this FOA:

Does the investigative team have the expertise to perform all planned experiments?

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?

Specific to this FOA:

How novel is the proposed approach for evaluating potential new treatments for mental illnesses?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA:

Evaluation of the approach should emphasize the biological rationale, the ability of the planned experiments to contribute towards building innovative and useful preclinical assays and approaches in a therapeutic development pipeline. Areas of particular importance include:

• How directly will proposed studies modify the circuits under investigation and record effects on circuit activity? How effectively will the experiments evaluate relationships between brain activity changes and physiological/behavioral assay measures?
• How well justified is the choice of neurophysiological and/or behavioral measures in terms of 1) potential relevance to functional deficits in humans with mental illnesses and 2) feasibility to perform the measure in animals in the current project and in humans in future studies?
• How strong is the rationale that supports conservation of brain processes and circuitry underlying the measures across humans and the preclinical species? How likely are the proposed experiments to provide the data necessary to determine whether the brain processes under study will allow future direct comparison with humans?
• How clear and well-justified are proposed go/no-go decisions for further measure development and implementation in a therapeutic discovery pipeline?
• For phase 2 studies, to what extent is the proposed design appropriate for the choice of drug/intervention, including dose range, route, PK sampling, and timing of the intervention in relation to testing? To what extent is the proposed dose selection based on brain target engagement measures such as receptor occupancy? To what extent are the proposed measurements based on known drug Cmax? How effectively will the proposed experiments test the involvement of hypothesized circuits in driving the physiological/behavioral assay measures?

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 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 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 Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) 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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals 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

For Renewals, the committee will consider the progress made in the last funding period.

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.

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

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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 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 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.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 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 Research Terms and Conditions
• 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 FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. 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.htmlandhttps://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 FOAs 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 $25,000.  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 Appendix XII to 45 CFR Part 75, 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 – Award Term and Conditions 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

Jamie Driscoll
National Institute of Mental Health (NIMH)
Telephone: 301-443-5288
Email: jdrisco1@mail.nih.gov

Sofiya Hupalo, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3752
Email: hupalos2@mail.nih.gov

Center for Scientific Review (CSR)

Email: FOAReviewContact@csr.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.