FAQs for PAR-23-091 Building in vivo Preclinical Assays of Circuit Engagement for Application in Therapeutic Development (R01 Clinical Trial Not Allowed)
1. What is the purpose of this FOA?
This initiative supports the development of innovative, non-invasive measures of brain activity for use as assays in the early screening phase of treatment development. Assay measures to be optimized and evaluated will reflect neurophysiological and/or behavioral processes that are directly relevant to functional domains that may be impaired in mental illnesses. Ultimately, the goal is to identify assay measures with a strong research-based rationale for inclusion in early phase preclinical screening of treatment development for predicting clinical effects in humans.
2. What are the key requirements for responsive applications?
All responsive applications must include the following phases:
- Optimization, in animals, of novel, predominantly non-invasive neurophysiological and/or behavioral measures reflecting activity of clinically relevant brain processes or functional domains that are disrupted within or across mental illnesses. While the neurophysiological/behavioral measures may not be innovative by themselves, their inclusion in a therapeutic development pipeline must be novel. Optimization should focus on mirroring testing parameters or measures used in human experiments where human assays exist, or developing tests that have the potential for future translation to parallel measures in humans.
- Evaluation of the performance of physiological and/or behavioral measures using FDA-approved drugs or other perturbations (e.g., closed loop stimulation) with demonstrated effects on the neurobiological targets hypothesized to modulate the assay measures. This phase should use a dose-ranging approach that includes pharmacokinetic/pharmacodynamic (PK/PD) readouts to measure the sensitivity of the assay.
- 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 in this phase are also expected to test the effects of the same perturbations used in the evaluation phase to assess the relationship between the assay measures and the neural circuits.
A study might propose to optimize an operant paradigm that is presumed to assess multiple aspects of anhedonia that are disrupted in patients with mood disorders.
- The optimization phase might involve modifications of existing methods to mimic rates of acquisition and performance of a comparable task in humans. For a study aimed at developing an assay of task driven spectral EEG signatures, the optimization phase might address technical barriers to maximize the ability to compare data from the rodent with human EEG measures in the future.
- The evaluation phase would involve administering a perturbation expected to affect the measure. In our example, a dopamine modulator might be given across doses to assess the sensitivity and responsiveness of the measure in this phase.
- The mechanistic testing phase would address the underlying biological rationale for focusing on the measure and the choice of perturbation. Perhaps in our example, a circuit including D1 dopamine receptor signaling is proposed to enable reward memory coding changes in dopaminergic neural activity. One can imagine several hypotheses using a combination of methods, including optogenetic stimulation or inhibition of dopamine neuron single cell recordings in the striatum during task performance.
3. What is meant by “predominantly non-invasive” measurements?
Some degree of invasive manipulation might be necessary in animals to measure processes that can be assessed non-invasively in humans. For example, human scalp EEG might be best modeled by invasive LFP recordings from animals in some cases
4. What if the circuits underlying the physiological or behavioral measure are already well established? For example, I want to develop an assay using changes in sleep spindles underlying learning as a dependent measure, but the circuits underlying this phenomenon are already well established. Do I still need to propose a mechanistic test of the circuit?
Yes, it is important to validate the physiological and/or behavioral measure and determine whether the response to perturbations is indeed mediated through the proposed circuits.
5. What if my mechanistic test fails to identify a critical circuit, would that suggest the assay measure is not useful?
Not necessarily, but it would suggest that the neurobiology behind the assay is not established, suggesting a need for caution in implementing it in a therapeutic pipeline. Ideally, alternate hypotheses are proposed that could be tested. The mechanistic validation component is included to eliminate the need to guess what a behavioral assay represents.
6. How many years may I request for the project?
The maximum duration is 5 years. All projects must propose a timeline and milestones they will implement to accomplish all 3 required components of the projects. A final milestone should outline plans and a timeline for dissemination of results, regardless of the outcome.
7. What does it mean to “Describe how the results will add value to a therapeutic development pipeline regardless of outcome?”
A plan needs to be in place for making the data available to the research community regardless of whether the work succeeds in identifying a novel potential assay, or if the suggested measure was sub-optimal for further development.
8. Are there any special considerations in selecting the preclinical species?
The FOA supports assay development around those measures that assess the highest level of shared function across species. In most cases, this will limit the selection of the preclinical species to mammals.
9. I would like to test a novel treatment candidate in animals. Is this research goal aligned with the intent of the FOA?
No. The main purpose of this FOA is to develop and evaluate novel brain-based measures as assays and not to evaluate new therapeutic targets or treatment candidates. Applications aimed at therapeutic development or clinical evaluation of novel therapeutics are directed to the FOAs listed on The NIMH Therapeutics Development website.
10. Can studies in humans be included?
No human studies are allowed for this FOA. However, the assay measures developed in animals through this FOA should be designed so the cross-species coherence, or lack thereof, of assay performance can be assessed in future projects. In this way, assays developed here may be considered the preclinical prequel to subsequent projects aimed at cross validating the assays against similar measures in healthy humans (see PAR-23-087; Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3) .
11. I am interested in developing and testing a physiological measure. Is it necessary to have the behavioral output as well?
No, a behavioral measure is not required.
12. Are stress manipulations or genetically modified animals appropriate manipulations for this FOA?
Perturbations used to evaluate the performance of the assay measures must be selected based on their potential for cross species evaluation in future studies involving humans, as well as the ability to evaluate more than one dose or level. Use of transgenic animals is appropriate in the mechanistic testing phase to selectively manipulate genetically defined neuronal populations and circuits. Use of stress manipulations may be appropriate to develop assay measures that will display sufficient sensitivity to perturbations.
13. Can preclinical disease models be included?
While use of transgenic animals is allowed, their use must be justified as to why they are preferable to wild-type animals in addressing the goals of this FOA. Applications proposing inclusion of animal models “of” mental disorders, broad battery of behavioral tests, or approaches that model human psychiatric diagnoses on the basis of face validity (e.g., depression- or anxiety-like behaviors) are not considered responsive to this FOA (for more information, see NOT-MH-19-053 ).
14. Are there any assay measures that are not appropriate for this FOA?
Studies aimed solely at developing measures of circadian rhythmicity or clock regulatory mechanisms as assays are not appropriate. In contrast, studies aimed at examining sleep microstructure in relation to learning and plasticity (spindles) would be encouraged. Likewise, studies focused solely on homeostatic functions including drinking, feeding, as well as reproductive behaviors are outside the scope of this FOA.
15. Are industry partners allowed?
Collaborations between academic and industry partners are encouraged as long as the data and protocol sharing plan goals can be maintained.
16. How is the evaluation of applications from foreign investigators different from U.S. investigators?
Non-U.S. institutions are eligible to apply, and collaborations with non-U.S. investigators are allowed. For applications submitted by 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. Additional information is available on the NIH Information for Foreign Grants page.