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:
- 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.
- 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.).
- 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.
Deadline: January 4, 2019 (letters of intent); February 4, 2019 (full proposals)
URL: https://grants.nih.gov/grants/guide/rfa-files/RFA-MH-19-235.html
Filed Under: Funding Opportunities