There has been a fundamental failure to translate preclinically-supported compounds into clinically-approved treatments. This failure generally reflects the profound differences between phenomenon assessed in the laboratory and those targeted in the clinic. Behavioral similarity is not enough to suggest translation. For novel treatments to emerge, they will require animal models with cross-species consistency. Hence, there is a critical need for: i) neurophysiological biomarkers of behaviors relevant to domains affected in psychiatric patients that; ii) can be conducted across species; and iii) that are alterd by drug treatment. Such biomarkers would prove stronger evidence that effective preclinical pharmacological manipulations could be effective clinical treatments. We developed the 5-choice continuous performance test (5C-CPT) to quantify cognitive control and response inhibition for use in rodents and humans. We also developed a probabilistic learning (PL) task for mechanistic understanding of reward learning across species. New endeavors here include the progressive ratio breakpoint procedure (PRBP), a task first developed to quantify motivation from physical effort and a rodent cognitive effort task (CET) both of which have recently been reverse-translated for human testing. In addition, action selection/preference-based decision making can be measured across species using the risky gains task (RGT), which quantifies responding to positive vs. negative feedback on a trial-by-trial basis. The UH2 component of this application (Specific Aim 1) will use electrophysiological biomarkers to test the following hypothesis across species: 5C-CPT 1A) Non-target (nogo) stimuli response levels (response inhibition) will inversely correlate with larger frontal event-related potential (ERP) components (e.g. P3a) and 1B) Parietal beta activity will correlate with the sensitivity index measure of cognitive control. PL 2A) the Reward Positivity ERP component, which scales with the degree of positive prediction error, will vary in strength according to probability ratio (80/20>70/30>60/40) and 2B) the strength of the Reward Positivity will correlate with the % correct within each ratio block. PRBP 3) Physical effort will be linked to frontal alpha power; CET 4) Hard cognitive effort choices will be linked to ACC activation as measured by frontal midline theta power. RGT 5A) A stronger mid-frontal theta oscillatory component (Feedback-Related Negativity) will correlate with shifting choices after punishment feedback while 5B) Parietal delta power (e.g. P3) locked to the imperative cue will correlate with the likelihood of staying at the same choice after reward Tasks fulfilling these hypotheses in both mice and humans will then move onto the UH3 component (Specific Aim 2) which will test whether elevating frontal dopamine levels via tolcapone treatment will influence behavior and neurophysiological markers during these tasks. For example, we would hypothesize that tolcapone would induce stronger frontal late ERPs and reduced response inhibition in the 5C-CPT, or increased ACC activation and hard-choice preference in the CET.

Public Health Relevance

Neurophysiological biomarkers of behavioral dimensions from cross-species paradigms. The translation of therapeutic evidence with positive preclinical support to clinically approved treatments has been overwhelmingly disappointing, at the cost of billions of dollars, time, effort, and the hope of the patients being tested. This failure has been driven primarily by poor cross-species relevant tasks with appropriate neurophysiological biomarkers measuring neural circuits relevant to the behavioral domain investigated. This project will develop tasks with accompanying biomarkers that can be tested in both mice and humans that quantify the behavioral domains of cognitive control, response inhibition, reward learning, both physical and cognitive effortful motivation, and feedback-driven decision-making processes.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
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Special Emphasis Panel (ZMH1)
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University of California, San Diego
La Jolla
United States
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