Background

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a new dynamic picture of the brain that, for the first time, will show how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat and prevent brain disorders.

NIH is one of several federal agencies involved in the BRAIN Initiative. Planning for the NIH component of the BRAIN initiative is guided by the long-term scientific plan, BRAIN 2025: A Scientific Vision, which details seven high-priority research areas and calls for a sustained federal commitment of $4.5 billion over 12 years. This funding opportunity announcement (FOA) and other FOAs issued as part of the BRAIN initiative are based on careful consideration by the NIH of the recommendations of the BRAIN 2025 Report, and input from the NIH BRAIN Multi-Council Working Group. Videocasts of the NIH BRAIN Multi-council Working Group are available at http://www.braininitiative.nih.gov/about/mcwg.htm.

To enable rapid progress in development of new technologies as well as in theory and data analysis, the BRAIN Initiative encourages collaborations between neurobiologists and scientists from statistics, physics, mathematics, engineering, and computer and information sciences; NIH welcomes applications from investigators in these disciplines.

Milestones and success criteria will be established to help determine if the tool/method development effort funded by this award should be continued or discontinued. If justified, future year milestones may be revised based on data and information obtained in the current year. In addition to milestones, the decision regarding continued funding will also be based on the robustness of the entire data package that adequately allows an interpretation of the results, overall progress, NIH BRAIN Initiative portfolio balance, program priorities, competitive landscape, and availability of funds. Therefore, continuation is based upon all available evidence at annual review that there remains a reasonable expectation that the project will achieve the goal initially judged to be meritorious by peer review.

NIH encourages BRAIN Initiative applications from investigators that are underrepresented in the biomedical, behavioral, or clinical research workforce (see data at http://www.nsf.gov/statistics/showpub.cfm?TopID=2&SubID=27 and the most recent report on Women, Minorities, and Persons with Disabilities in Science and Engineering). Such individuals include those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds.

NIH also encourages businesses to participate in the BRAIN Initiative. It is possible for companies to submit applications directly to BRAIN Initiative program announcements or to collaborate with academic researchers in joint submissions. Small businesses should consider applying to one of the BRAIN Initiative small business FOAs (http://braininitiative.nih.gov/funding/index.htm).

In addition to the National BRAIN initiative, the NIH continues to have a substantial annual investment in neuroscience research. The Institutes and Centers contributing to the NIH BRAIN Initiative (http://braininitiative.nih.gov/ ) support those research efforts through investigator-initiated applications as well as through specific FOAs. Potential applicants to this FOA are strongly encouraged to contact Scientific/Program staff if they have any questions about the best FOA for their research.

The BRAIN Initiative will require a high level of coordination and sharing between investigators to achieve its goals.

This FOA is related to the Recommendations in Section III.1 and 2 of the Final Report (http://www.nih.gov/science/brain/2025/index.htm) of the BRAIN working group. Specifically, this FOA solicits applications that will address the recommendations on "Discovering Diversity" and "Maps at Multiple Scales", (Section III).

Research Objectives

This FOA is designed to support development and validation of novel tools to facilitate the detailed analysis and/or manipulation of cells and circuits and provide insights into the neural circuitry and structure underlying complex behaviors in humans and non-human primates and other mammalian brains (e.g., sheep, pig). The human brain consists of an estimated one hundred billion neurons and similar number of supporting glial cells that are uniquely organized to confer the extraordinary computational activities of the brain. Considerable progress has been made in defining the cytology and signal transduction processes in the CNS, but circuit-level function and the neural mechanisms of cognition and behavior remain poorly understood. Cell-type and circuit-specific manipulation strategies are key technical factors in addressing these important areas and represent attractive strategies to treat brain disorders. This initiative is focused on developing tools (or vastly improving existing tools) that will ultimately enable access to individual cells and defined groups of cells within neuronal circuits of the human brain. In order to achieve these goals, it is acknowledged that the use of large brains such as non-human primates, sheep and pig will be instrumental in this process. Development of tools that are applicable to human or non-human primate brains should focus on overcoming barriers to use of such tools (i.e., opto/chemo and magnetogenetic acutators). The tools sought through this FOA can include novel genetic or non-genetic methods for targeted delivery of genes, proteins, and chemicals to specific cells or tightly defined cell types and circuits.

Development of novel tools that will delineate anatomical connections between cells and expand our knowledge of circuit architecture and function is an area well poised for additional investment. Several efforts are currently underway to study large-scale, long-range connections, such as the NIH Human Connectome Project, as well as large scale rodent connectional studies. Recent development of innovative technologies (e.g., CLARITY, expansion microscopy, MERFISH, and several other imaging breakthroughs) allows an unprecedented three-dimensional view into the post-mortem brain. While still at an early stage, these exciting technologies hold promise for mapping short- and long-range connections throughout the brain. Coupled with improved activity monitoring technologies in awake, behaving animals, these new tools promise an understanding of circuitry in action. Further development of these technologies is crucial to push the envelope beyond our current capabilities. To this end, applicants from the biological sciences are encouraged to establish collaborations with engineers, chemists, material scientists, nanobiologists, and colleagues in other disciplines to develop groundbreaking approaches to study brain activity.

This FOA solicits applications to develop next-generation, innovative technologies to define and target specific cell types in the large mammalian and non-human primate brain. Of high importance are first-in-class and/or cross-cutting non-invasive or minimally invasive techniques that permit repeated measurements from and manipulations of cells over time in a non-destructive manner.

Tools/technologies relevant for this initiative are expected to be transformative, either through the development of novel tools that may be high-risk or through major advances in current approaches that break through technical barriers and will significantly improve current capabilities. While an emphasis of the BRAIN initiative is the development of novel tools to study the brain, here we highlight the need for innovative approaches to bridge experimental scales. Studies that can explore molecular and cellular mechanisms of neural activity permitting improved precision and sensitivity in the analysis of micro-and macro-circuits are strongly encouraged. Progress in understanding how the activity of the brain translates to complex behaviors will be facilitated by non-invasive approaches for both monitoring and manipulating neural activity in awake, behaving mammals. The ultimate practical goal of this FOA is to move these tools in to practice. The phased award will be dependent on milestones proposed by applicants and agreed upon at time of award. Validation of methods or tools in other organisms will only be considered responsive during the UG3 phase of the award and should focus on feasibility measures to move into human or non-human primate models during the UH3 phase. Milestones must be proposed that will demonstrate feasibility for moving into large brains during Year 3 of the award. The new tools and technologies should inform and/or exploit cell-type and/or circuit-level specificity. Plans for validating the utility of the tool/technology will be an essential feature of a successful application and applicants are expected to address issues related to safety, stability, reliability etc. The development of new genetic and non-genetic tools for delivering genes, proteins and chemicals to cells of interest or approaches that are expected to target specific cell types and/or circuits in the nervous system with greater precision and sensitivity than currently established methods are encouraged. Methods to track and monitor exogenously delivered constructs for brain targeting and circuit manipulation are also desired goals. Applications that provide approaches that break through existing technical barriers to substantially improve current capabilities are highly encouraged.

Applications using invasive devices for recording or stimulating neural activity in the human brain should consider one of the following BRAIN Initiative FOAs, and should contact the listed research contact to discuss the appropriateness of the project:

RFA-NS-18-021: BRAIN Initiative: Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (UG3/UH3 Clinical Trial Required)

RFA-NS-18-023: BRAIN Initiative: Clinical Studies to Advance Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (UH3 Clinical Trial Required)

RFA-NS-18-022, BRAIN Initiative: Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (U44 Clinical Trial Required)

Research Scope

This FOA will support the phased development and validation of novel tools to facilitate the detailed analysis and/or manipulation of cells and circuits and provide insights into the neural circuitry and structure underlying complex behaviors in humans and non-human primates. Support will be provided for the initial development phase and can be continued through the validation and application phase if a rigorous set of milestones are achieved. For all tools and methods proposed, applicants should address issues related to safety stability, reliability and/or other relevant topics that may be barriers to adaptation in human or non-human primate brains.

This FOA seeks applications in areas including, but not limited to:

• Improving the stability, reliability, or safety of circuit therapeutic tools for use in large animal brains (including sheep, pig, and primate models).
• Novel methods with high safety profiles to deliver actuators (non-genetic and genetic) that are cell- and circuit-specific in human and non-human primates.
• Novel conditional intersectional tools that are both activity- and cell-specific.
• Novel methods for tagging individual neurons such that cellular components of a functional circuit can be explored.
• Adaptation, refinement and validation of gene delivery systems for targets in large brains (e.g., human and non-human primate).
• Chemical or genetic engineering of blood brain barrier-crossing carrier agents (such as tagged antibodies or other tools) to allow delivery of specific cargoes (e.g., neuronal actuators, effectors, tracers or sensors) to specific cells or circuits.
• Novel methods for non-invasive targeted access to, or manipulation of, distinct cell types in defined circuits with spatio-temporal control.
• Novel trans-synaptic tracers that can work in retrograde and anterograde direction or deliver cargoes to cells in the nervous system.
• New methods to trace cell lineage to understand how circuits develop.
• Enhanced temporal and spatial resolution techniques for noninvasive molecular imaging of neuronal cells for in situ brain studies.
• Unique combinations of tools for multiplex analysis and/or manipulation of single cells in situ to maximize data content over many parameters (e.g., RNAs, proteins, metabolites, organelles, electrochemical dynamics, signal secretion/reception/transduction, cytoarchitecture or migratory changes).
• Innovative tools that provide significant advances in sensitivity, selectivity or spatiotemporal resolution of molecules/structures/activities within single cells in the brain and between ostensibly similar cells in situ (e.g., high resolution imaging of molecular interactions within single cells).
• Novel automated and scalable assays for high-throughput analysis of single cells in situ in the brain, including scalability of measured parameters in parallel, cell numbers and/or speed of processing.
• New tools and approaches that minimize tissue and cell perturbations so that cell viability is maintained, allowing for multiple repeated measures in the same cell over time.
• Novel methods for visualizing or manipulating epigenomic marks or gene expression in neural cells.
• Innovative approaches to bridge scales of experimental approach. Studies that can explore molecular and cellular mechanisms of neural activity in broader contexts are encouraged.
• Innovative molecular complementation methods to identify synaptic connections and determine their phenotypes.
• Development of cell type-specific molecular sensors and additional tools and approaches to address circuit-specific manipulation and monitoring. Validation could include behavioral measures.
• Generation of genetic modifications that express cell type-specific labels such as fluorescent indicators or other markers.

Applications will be considered non-responsive and will not be reviewed if they propose:

• To develop tools or approaches that use organisms other than large brain mammals or non-human primates, except in the UG3 phase where some feasibility studies may be warranted.
• Studies to develop transgenic models of disease.
• Projects whose main goal is to address a scientific question(s).

The UG3/UH3 is a two-phased award. The UG3 phase should be focused on the development of the tool, method, or approach, including demonstrating feasibility for use in humans. Each phase will be milestone driven and only those projects attaining the UG3 milestones have potential to progress to the UH3 phase. The UG3 phase supports feasibility, safety, biocompatibility testing and optimization of tools in large brains (e.g., sheep, pig) as well as non-human primates and humans if possible. The initial UG3 phase could support non-clinical testing toward filing of an IND/IDE for a significant risk (SR) study or to obtain IRB approval for a non-significant risk (NSR) clinical trial. Only those UG3 projects that have met specific criteria (see below) will transition to the subsequent UH3 phase after NIH administrative review. The UH3 phase could support a small clinical trial. The UH3 phase supports testing/validation of the tools in efforts to evaluate the performance, sensitivity, and selectivity of the tool(s) in humans or non-human primates.

1. UG3 Tool Development Phase

The UG3 Phase of this FOA supports milestone-driven tool development. The applicant should describe the specific tool, its potential, and what developments are required to translate the tool to larger animal or human brains. Tools that meet the scientific milestones and feasibility requirements will be eligible for transition to the second UH3 stage pending NIH administrative review, availability of funds, and programmatic balance as described below. For applications wishing to perform human studies in the UH3 phase, a detailed regulatory pathway pre-clinical testing plan with commensurate milestones must be included. Regulatory milestones include pre-submission meetings where pre-clinical testing is discussed with the FDA as well as further pre-IND/IDE meetings. Relationships with industry partners that may be necessary for clinical testing should be described. An IND/IDE will be required for the UH3 transition prior to the start of any clinical trials.

2. UH3 Tool Evaluation and Validation Phase

The UH3 Phase of the FOA will support milestone-driven evaluation and validation of tool performance. This phase should evaluate the tool's capability as well as performance in the context of large brains. Capability can be demonstrated by the ability to target, manipulate, record, or otherwise impact brain circuitry in a measurable fashion. Performance should be evaluated by the tool's stability, safety, reliability, or other similar metrics tested within a large brain construct. Validation should extend the tool's use outside of the primary investigators' lab to assess performance across multiple constructs. Different variants within a species and trans-species testing may be used to demonstrate generalizability. While not required for this FOA, applications that propose independent evaluation of the tool by outside laboratories will be prioritized. For applications proposing clinical studies, detailed milestones focusing on patient recruitment, retention, safety, and performance metrics should be included.

Applicants are strongly encouraged to consult the appropriate Scientific/Research Contact, listed below, to discuss the alignment of their proposed work with BRAIN Initiative Program goals.

Milestones and Go/No-Go Criteria

Because tool/technology development in the UG3 phase is likely to be high risk, it is anticipated that there will be attrition of some projects after the development phase (UG3). Objective milestones of success and go/no-go rules for tool optimization/validation will be required and both should have quantitative criteria associated with them (see Section IV.2 for details). Milestones are defined as annual goals while the Go/No-Go criteria are defined as the major goals to be met to inform the UG3 to UH3 transition.

Specific Go/No-Go criteria should be detailed at the UG3 to UH3 phase transition. Projects that seek to test first-in-human during the UH3 phase should have regulatory approval as their major Go/No-Go criteria. Projects that will focus on animal-model validation in the UH3 should detail specific performance metrics to be obtained in the UG3 phase prior to transition.

NIH program staff will contact the applicant to discuss and negotiate the proposed milestones and any changes recommended prior to funding the application. The final agreed upon and approved milestones will be specified in the Notice of Award (NoA). Progress towards achievement of the final set of milestones will be evaluated by NIH program staff. Program staff may involve independent consultants with relevant expertise. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project will be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, portfolio balance and program priorities, competitive landscape, and availability of funds.

NIH encourages increasing the rigor and reproducibility of observed results. In some cases, conducting additional critical experiments will be important for NIH to have confidence in making a funding decision. Therefore, program staff may suggest modification or additional experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds.

UG3 phase to UH3 phase transition:

An administrative review will be conducted by program staff, with potential input by independent consultants, to decide whether a UG3 phase project will be transitioned into the UH3 phase based on the:

• successful achievement of the defined milestones for the UG3 phase of the project;
• likelihood of success in further pre-clinical/clinical validation testing;
• competitive landscape;
• program balance;
• availability of funds;
• for significant risk studies, submission of an IND/IDE for the clinical trial with documentation of final or conditional approval of the IDE from the FDA;
• IRB approval(s), if necessary;
• for clinical studies, submission of the final clinical protocol and supporting documents to NIH for administrative review, and notification of approval by NIH;
• feedback on activities involving human subjects obtained from relevant NIH human subject protection bodies;
• agreement on updated timeline, milestones and budget for the UH3 phase

Appeals of the transition decision will not be accepted.

Protection of Human subjects: Applications with data collection plans that involve multiple respondent groups (e.g., clients/patients, therapists/providers, supervisors, administrators) should address provisions for human subject protections and consenting procedures for all participant groups, accordingly. The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-15-025). The application’s Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations.)

Appeals of the transition decision will not be accepted.

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government -including the NIH Intramural Program
• 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)

Applicant organizations

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

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

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

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

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

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

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. 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 NOT-OD-11-101)

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. 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. 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 the UG3 and UH3 phases. All applications are required to include both UG3 and UH3 phases.

Research Strategy: Organize the Research Strategy in the subsections identified below, addressing all specific points below.

UG3 Tool Development Phase

The specific improvements to be made, such as stability, reliability, safety, should be described in detail. Applicants should provide a detailed plan that includes critical steps required for successful development of their tool. UG3 projects are milestone driven and include milestones' criteria for each proposed tool, or stage of development if appropriate that will be used to determine whether there is likelihood for successful translation to larger brain.

Applicants should describe both the UG3 phase and the UH3 phase within these subsections as described, including milestones.

Significance:

• Discuss the need for the tool to further research in human and non-human primate brain
• Describe ways in which the tool(s) will advance the field
• Does the tool or technology confer a high degree of cell or circuit-specificity? Has the current state of the art been accurately described? Would the proposed tool significantly advance current capabilities? Does the tool have the potential to be applied in humans? Will the proposed study be significant to developing and validating novel tools to analyze cell-specific and circuit-specific processes in the human brain?

Innovation:

• Explain how the project offers a novel approach to monitor and manipulate brain activity in human and non-human primate brain
• Discuss feasibility to overcome current obstacles
• Does the proposed work address existing barriers?
• Will the proposed tool enable discovery related to brain circuitry underlying complex behaviors?
• Are the proposed tools/technologies potentially transformative either through the development of novel tools that may be high-risk or through major advances in current approaches that break through technical barriers and will significantly improve current capabilities?

Approach: This section should cover the application, as a whole, as well as the UG3/UH3 phases with the appropriate headers within the text.

• Are the appropriate studies included to validate the technology?
• Is a sound rationale provided as to why the approach proposed is the most appropriate and is likely to generate an exceptionally high impact if successful?
• Does the application address issues related to safety, stability, reliability and/or other relevant topics that may be barriers to adaptation in human or non-human primate brains?

Current State-of-the-Art Statement: Investigators should specifically define the current state of technology as a benchmark against which their proposed groundbreaking technology or improvements will be measured. Preliminary/feasibility data are not required or expected for early-stage, high-risk projects. However, a sound rationale should be provided as to why the approach proposed is the most appropriate and likely to generate an exceptionally high impact if successful. In these cases, more emphasis should also be placed in details of the approach, particularly feasibility-testing. Applicants are expected to explain the specific biological assay(s) to be utilized in the application to validate the new tool in proof-of-concept testing. Applicants are expected to address if proposed tool(s) have the potential to be applied in multiple model species. The tools should enable analysis of brain circuitry underlying complex behaviors.

Project Timeline (Gantt chart): A project timeline should be included as part of the Research Strategy and should include a distinct final section, entitled Milestones , that briefly proposes indicators of progress at critical junctures. These should be tailored to the unique scope of each project and written concretely enough to evaluate what exactly will have been achieved (e.g., crucial steps in tool making) over the duration the project. Given that projects are likely to be early stage and high-risk in nature, this should include the specific proof-of-concept test(s) that will indicate whether/how a proposed tool actually works , along with alternative strategies should that effort fail to perform as expected. Tests should include a comparison against existing benchmark technologies; if a tool is truly first-in-class, comparisons may be done against a nearest neighbor technology. Investigators should briefly note how results will be used to inform future phases of tool development such as testing in other model systems or in non-human primate or human brain. Note: This timeline is distinct from the Clinical Trials Study Timeline (if applicable).

Milestones: As part of the application, projects should include quantitative milestones and go/no-go decision points. Applicants must describe milestones to be used for measuring success in achieving each of the research plan's objectives. One or more milestones should be used for each objective. Details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured) should be included for each milestone. Applicants are expected to include quantitative criteria for measuring success and the rationale for the quantitative criteria. Quantitative criteria should be robust and consistent with the state-of-the-art in the field. Each milestone must have a timeline, and be incorporated into the overall project timeline, which should also be reflected in a Gantt chart. There should be at least one milestone proposed for completion at the end of each year. Strategies for alternative approaches should be discussed in detail. Technology development is inherently risky, but probability of success is greatest when potential hurdles are anticipated and contingency plans are in place. A Milestone report from the Principal Investigator will be submitted to the NIMH Grants Management Branch 60 days before the Budget End date. The Milestone report will be included in the non-competing year progress report via RPPR. Please note that milestone/progress reports should include an executive summary of progress and milestone achievement, followed by a more detailed description of progress which explains and justifies the use of all selected study parameters or objectives, including but not limited to, number of animals used per study (stratified by gender if applicable), statistical analysis used and assumptions, rules for inclusion/exclusion of animals or data, randomization/blinding details, before demonstrating how study results conform or corroborate each parameter or objective. This information will be used by NIH program staff to evaluate the overall robustness of the data package and path forward.

Applications lacking clearly described timelines for the UG3 and the UH3 phase, as well as Milestones will be considered incomplete and will not be reviewed.

While it is understood that many tools will be at an early proof-of-concept stage, a central goal of this FOA is to generate transformative tools that will be widely used throughout the research community. Applications that propose to generate such tools are expected to include a detailed plan for sharing these resources and expected to include the following key elements:

• Project management of resource sharing;
• Description of what specific resources will be shared (e.g., model organisms, reagents, completed tools or repurposed components);
• Schedule/timeline for availability of resources to other users;
• Persons who will have access to the resources (written as broadly as possible to the extent consistent with applicable laws, regulations, rules, and policies);
• Plan for post award disposition of resources.
• Investigators are strongly encouraged to obtain a research resource ID from the Resource Identification Initiative (http://scicrunch.com/resources/info/add) and to use Resource IDs in their publications if available. (http://scicrunch.com/resources ).

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving NIH-defined human subjects research, clinical research, and/or 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.

All instructions in the SF424 (R&R) Application Guide must be followed. Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy. 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.

While it is understood that many tools will be at an early proof-of-concept stage, a central goal of this FOA is to generate transformative tools that will be widely used throughout the research community. For applications that propose to generate such tools, does the application include an adequate and detailed plan for sharing these resources as appropriate and consistent with achieving the goals of the program? Does the plan provide a strong rationale for each of the following key elements as appropriate and consistent with achieving the goals of the program?

• Project management of resource sharing;
• Description of what specific resources will be shared (e.g., model organisms, reagents, completed tools or repurposed components);
• Schedule/timeline for availability of resources to other users;
• Persons who will have access to the resources (written as broadly as possible to the extent consistent with applicable laws, regulations, rules, and policies);
• Plan for post award disposition of resources.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Overseeing all aspects of the award including management of resource sharing, preparing comprehensive progress reports, scheduling meetings with NIH program staff, and other duties as necessary.

• Defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
• Developing and proposing rigorous milestones that will be achieved during the project period.
• Retaining custody of and having all rights to the data and technology developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Pursuing patent protection, as appropriate and consistent with the terms and conditions of the award and goals of the program.
• Providing quarterly progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not.
• In cases when NIH program staff request raw data, awardees agree to provide the data.
• Participating at least twice a year in progress meetings (teleconferences) that are organized by NIH staff.
• Communicating regulatory meeting dates and agenda to the NIH program staff and invite their participation.
• Communicating study reports from Clinical Research Organizations (CROs), meeting minutes (and associated data packages if applicable), letters and other forms of communications with FDA, Recombinant DNA Advisory Committee (RAC), and other authorities, and to provide IND number and registration numbers in clinical trial.gov, if applicable.
• Providing regulatory and clinical documents that are required for administrative review.
• Verifying that the clinical trial (if applicable) is performed in accordance with Good Clinical Practices (GCP) and all IC specific guidelines for data and safety monitoring in clinical trials (e.g. NINDS Guidelines for Data and Safety Monitoring in Clinical Trials: http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm, and must provide data and regular updates to NIH.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIH Project Scientist(s) will have substantial scientific/programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
• NIH Project Scientist(s) provides input on the milestones and makes recommendations regarding their finalization.
• NIH Project Scientist(s) will be responsible for assessing the progress of the project towards the specified milestones, and for advising the Program Officer about whether further funds should be released to the project.
• NIH Project Scientist(s), in consultation with the PIs, may suggest modification or additional experiments to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NIH.
• NIH Project Scientist(s) participates in meetings together with PIs with regulatory agencies related to the funded project.
• Additionally, an NIH Program Officer will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• The Program Officer, with advice from others managing the BRAIN Initiative, will make decisions on project continuation based on staff recommendations, programmatic prioritizations and budget considerations. NIH program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIH portfolio balance and program priorities, competitive landscape, and availability of funds.

Areas of Joint Responsibility include:

Clarifying and negotiating the milestones and timelines. Creation of a steering committee if warranted.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee for the investigators chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16. Final decisions made by NIH regarding a discontinuation are not appealable.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Douglas S. Kim, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-6463
Email: [email protected]

Nick Gaiano, Ph. D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: [email protected]

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: [email protected]

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.