Locomotor Activation and Mania Spectrum Risk: Circadian and Reward Mechanisms

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ABSTRACT Bipolar spectrum disorders [BSD] are impairing and costly psychiatric conditions that typically emerge in late adolescence and early adulthood. Subthreshold mania symptoms, increasing in severity over the span of months-to-years, remain the most important symptomatic precursor of future BSD onset. However, only a subset of young people with subthreshold mania symptoms transition to a BSD and, regardless of later clinical diagnosis, these symptoms severely impact real-world functioning and clinical outcome. While early treatment of subthreshold mania symptoms appears increasingly imperative for a favorable prognosis, these symptoms are difficult to distinguish from other psychiatric conditions. Too often, delayed symptom recognition results in detrimental treatments and poor prognosis. Even if mania symptoms are correctly identified, it is unclear which individuals will progress to a more severe course and thus require more intensive early treatment. As a result, there remains a pressing clinical need to identify objective biobehavioral risk markers that will improve prevention and intervention for the full mania spectrum. Psychomotor activation - increased activity or energy - is a cardinal feature of the mania spectrum that can be quantified through objective measurement of locomotor activity. In a comprehensive laboratory assessment and naturalistic follow-up study, we propose to uncover the biobehavioral (circadian, reward) mechanisms driving locomotor activation and mania spectrum risk. We will recruit N=170 adolescents and young adults aged 16 to 24 years-old across a range of lifetime subthreshold mania symptoms but with no prior history of a BSD. Participants will complete 2 weeks of field-based locomotor activity monitoring with wrist actigraphy, followed by a comprehensive lab-based assessment of exploratory locomotor behavior, circadian function, and reward sensitivity. Over follow-up, actigraphic locomotor activity and clinical status will be indexed prospectively every 6-months for up to 3-years. Our primary aims will test the overarching hypothesis that locomotor activation is a behavioral marker of mania symptom severity and progression [Aim 1], and that neurobiological dysregulation of the circadian and reward systems drive locomotor activation [Aim 2] and mania symptom progression over time [Aim 3]. We will use high-dimensional modeling approaches to identify multivariate locomotor, circadian, reward profiles predictive of mania symptoms and their progression over time, which will inform more comprehensive biobehavioral predictive models for the mania spectrum. Exploratory analyses will 1) incorporate more nuanced locomotor metrics from a novel reverse-translational open field task and 2) examine the specificity of our model to mania vs other clinical outcomes. Our results have the potential to 1) improve early detection of mania symptoms through real-time, objective locomotor activity monitoring and 2) provide mania-relevant circadian and reward targets for behavioral, chronotherapeutic, or neuromodulatory interventions that alleviate or prevent mania symptoms more effectively than current best-practice approaches.