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 for 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 (NIMH Strategic Plan for Research) 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 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 recently 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, novelty induced feeding suppression, 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 and pharmacodynamic responses. However, these measures do not reflect specific neural processes or predict efficacy and 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 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 solicits 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 and/or 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.

All responsive applications must 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 as potential assays in a therapeutic pipeline across a range of perturbations (e.g., drugs, transcranial magnetic stimulation, etc.).
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.

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

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, and 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 with different frequencies.
• Measures that tap into fundamental processes that are disrupted within or across mental illnesses such as aspects of vigilance, neurophysiological measures of neural plasticity, or attentional mechanisms contributing to cognition and/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 vs 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 if 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 be 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, it is imperative that proposed neurophysiological and behavioral assay measures be feasible to perform in healthy humans.

Projects Not Responsive to this Announcement Include:

• Development or inclusion of animal models "of" mental disorders. Only wild-type healthy animals should be included in all phases except for genetic tools needed to measure and evaluate brain pathways relevant to the physiological or behavioral measures in the mechanistic testing phase 3.
• Broad batteries of behavioral tests to address emotional constructs such as depression or anxiety .
• 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.
• Studies in 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 must 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 vs cued fear learning.

Milestones

All projects must propose a timeline for completion of the required components of assay development, including assay measure optimization (1), evaluation of assay performance (2), and mechanistic testing (3). 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.

Technical Assistance Teleconference

A Technical Assistance teleconference will be held for potential applicants on January 8, 2019 at 2 PM EST. The dial in number is 866-755-6381 (88-33-299). NIH staff will be available to answer questions related to this FOA. Questions gathered via email and on these technical assistance calls as well as their responses can be found at: FAQ website.

Section II. Award Information

Section III. Eligibility Information

1. Eligible Applicants

• Public/State Controlled Institutions of Higher Education
• 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 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)

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

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

• 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 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.

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

3. Additional Information on Eligibility

• 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)

Section IV. Application and Submission Information

1. Requesting an Application Package

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not b inding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:
Email: [email protected]

It is expected that the PD/PI or each PD/PI on a multiple PD/PI application will dedicate at least 15% level of effort (1.8 person months) to managing the project.

Specific Aims: Provide the overall goals for the entire application. The Specific Aims section should include distinct Aims for each of the three phases. All applications are required to include all three phases.

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 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.
• Comment on the novelty of proposed assays.

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.
• 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.
• Explain the rationale behind the choice of preclinical species, assays, and endpoints for all studies.
• Describe goals for each of the three phases:
  • For step 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 step 2, performance evaluation; detail how performance of the physiological or behavioral measure(s) will be evaluated as potential assay(s) across a range of levels (i.e., doses) of a perturbation (e.g., drugs, transcranial magnetic stimulation, etc.). Describe the rationale for the perturbation selected for evaluation of the measure including dose, route, and timing of intervention in relation to testing. For example, if the perturbation is a drug, detail if dose selection is based on brain target occupancy.
  • For step 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 perturbations 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 sufficient 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 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 4 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.

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data 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 should 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.

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

4. Submission Dates and Times

5. Intergovernmental Review (E.O. 12372)

6. Funding Restrictions

7. Other Submission Requirements and Information

Section V. Application Review Information

1. Criteria