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Building in vivo Preclinical Measures of Circuit Engagement for Therapeutic Development


Lois Winsky, Ph.D.
Division of Neuroscience and Basic Behavioral Science


The primary goal of this initiative is to develop non-invasive measures of brain activity in preclinical species for assessing functional domains that may be impaired in mental illnesses. If successful, the preclinical measures developed under this initiative could be employed as proof of concept assays for advancing compounds and devices in the therapeutics pipeline for the treatment of mental illnesses.


Despite large investments by pharmaceutical and the biotech industries, the last 20 years have yielded very few novel treatments to address unmet needs for individuals with mental illnesses. Multiple factors have contributed to the low success rate, including insufficient understanding of both disease pathophysiology and the basis for heterogeneity in presentation and treatment response of patients within categorical diagnoses. The NIMH Research Domains Criteria (RDoC) begins to address these issues by providing a context to examine functional domains in humans. However, no parallel efforts are in place to identify and test potentially translatable measures across species included in the therapeutic development pipeline even though the poor predictive value of preclinical models and assays is well recognized by the pharmaceutical industry and academia (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 ). The goal of this initiative would be to support the discovery and testing of innovative neurophysiological measures in animals as potential assays for the therapeutic development pipeline. Promising measures developed through this initiative would be considered as the preclinical prequel to subsequent projects aimed at evaluating the performance of assays for coherence between preclinical species and healthy humans (e.g., PAR-16-065 ; Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3).

Projects responsive to this initiative would develop assays in animals in three steps:

  • Identify and optimize novel, non-invasive neurophysiological measures in animals that reflect fundamental processes that are relevant to mood or cognition such as aspects of vigilance, neural plasticity, reward processing, response inhibition, or attentional processes. Measures must be amenable for study in awake behaving animals and in humans. Examples include, spectral EEG or MEG to assess brain rhythms with different frequencies, sleep spindles. Innovative measures are encouraged.
  • Validate physiological measures: Evaluate coherence of neurophysiological measures with brain processes and/or circuits hypothesized to underlie the assay measures by in vivo manipulation and direct measurement of underlying brain circuits. Appropriate methods would include in vivo electrophysiological recording or intracellular calcium imaging in combination with optogenetic or chemogenetic approaches to localize brain pathways contributing to specific neurophysiological measures. For example, a study proposing prefrontal gamma oscillations as a physiological measure of reward-driven changes in executive function might include stimulation and recording of dopaminergic neurons projecting to prefrontal cortex to evaluate relationships between EEG power spectra and underlying circuits. 
  • Evaluate assay performance: Test and compare the response of the neurophysiological assay measure and the in vivo electrophysiological measurements of underlying brain activity in response to perturbations (e.g., drugs, transcranial magnetic stimulation). Studies would assess sensitivity, selectivity, and test-retest stability.