Key Dates

Reissue of PAR-19-289 - Building in vivo Preclinical Assays of Circuit Engagement for Application in Therapeutic Development (R01 Clinical Trial Not Allowed)

NOT-MH-22-210 - Notice of Intent to Publish a Funding Opportunity Announcement for Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3 Clinical Trial Optional)

National Institute of Mental Health (NIMH)

The National Institute of Mental Health (NIMH) intends to publish a Funding Opportunity Announcement (FOA) to solicit applications to identify, in animals, in vivo neurophysiological and behavioral measures for use as assays in the early screening phase of treatment development. This FOA will be a reissue of PAR-19-289.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects.

The FOA is expected to be published in Spring 2022 with an expected first application due date of October 5, 2022.

The FOA will utilize the R01 activity code. Details of the planned FOA are provided below.

Consistent with the objectives of PAR-19-289, studies appropriate for the FOA will optimize and evaluate measures of neurophysiological and behavioral processes that may serve as surrogate markers of neural processes of clinical interest based on available knowledge of the neurobiology of mental illnesses. The screening assays thus developed from the FOA are expected to build upon systems neurobiology and clinical neuroscience to enhance the scientific value of preclinical animal data contributing to a therapeutic development pipeline by assessing the impact of therapeutic targets and treatment candidates on neurobiological mechanisms of clinical relevance to mental illnesses.

The objectives of the FOA will be accomplished by supporting basic and translational neuroscientists who are committed to improving the efficiency and scientific value of the therapeutic development pipeline by advancing the discovery of in vivo physiological and behavioral measures reflecting circuit engagement as tools for early phase target validation and therapeutic screening for mental illness treatment development. The efforts supported by the initiative focus on measures in animals as a first step in generating translational assay measures that are adaptable across early therapeutic screens in animals to evaluation in humans. The FOA may be considered a prequel to build a suite of assays that are evaluated in future projects for coherence of assay performance between the preclinical species and healthy humans. The FOA will support efforts to improve the tool kit of assays available for early phase testing of novel therapeutic agents by incorporating measures proximal to neural systems that impact mental health.

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.

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 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.

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 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 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.

A companion UG3/UH3 FOA will also be released (see NOT-MH-22-210, reissue of PAR-19-214).

TBD

Applications are not being solicited at this time.

Please direct all inquiries to:

Jamie Driscoll

National Institute of Mental Health (NIMH)

301-443-5288

[email protected]