Locomotor Activation and Mania Spectrum Risk: Circadian and Reward Mechanisms

运动激活和躁狂谱系风险：昼夜节律和奖励机制

• 批准号: 10642785
• 负责人: Adriane M. Soehner
• 金额: $ 67.17万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642785
• 关键词: Adolescence; Adolescent; Adolescent and Young Adult; Amygdaloid structure; Animals; Anterior; Automobile Driving; Behavior; Behavioral; Biological; Circadian Dysregulation; Circadian Rhythms; Clinical; Clinical assessments; Data; Detection; Diagnostic; Disease; Dorsal; Early Diagnosis; Early treatment; Ensure; Feeling suicidal; Follow-Up Studies; Functional Magnetic Resonance Imaging; Future; Human; Hypersensitivity; Impairment; Individual; Intervention; Joints; Laboratories; Light; Manic; Measurable; Measurement; Measures; Mediating; Melatonin; Mental Depression; Modeling; Monitor; Moods; Motivation; Motor; Motor Activity; Neurobiology; Online Systems; Onset of illness; Outcome; Participant; Patients; Pattern; Persons; Phase; Photoreceptors; Population; Prevention; Production; Prognosis; Protocols documentation; Recording of previous events; Research; Rewards; Risk; Risk Marker; Sampling; Severities; Signal Transduction; Sleep; Specificity; Symptoms; System; Testing; Time; Ventral Striatum; Wrist; actigraphy; aged; behavior prediction; biobehavior; bipolar spectrum; circadian; clinical diagnosis; cost; diaries; emerging adult; follow-up; high dimensionality; hypomania; improved; indexing; motor behavior; neuroregulation; novel; novel strategies; predictive modeling; prevent; prospective; prospective test; recruit; response; reward expectancy; substance use

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.

抽象的 双极光谱障碍[BSD]是损害且昂贵的精神病疾病，通常在较晚出现 青春期和成年早期。亚阈值躁狂症症状，在整个跨度上的严重程度增加 逐年，仍然是未来BSD发作的最重要的症状前体。但是，只有一个子集 阈值躁狂症症状过渡到BSD的年轻人，无论以后的临床诊断如何 这些症状严重影响了现实世界的功能和临床结果。同时早期治疗 亚阈值躁狂症症状对于有利的预后似乎越来越需要，这些症状是 很难与其他精神病疾病区分开。经常，延迟症状识别会导致 有害治疗和预后不良。即使正确识别躁狂症症状，也不清楚哪个 个人将进入更严格的过程，因此需要更深入的早期治疗。因此， 仍然有紧迫的临床需求确定客观的生物行为风险标记，以改善预防 和全部躁狂谱的干预措施。精神运动激活 - 增加活动或能量 - 是红衣主教 可以通过客观测量运动活性来量化躁狂谱的特征。在 综合实验室评估和自然主义后续研究，我们建议揭露生物行为 （昼夜节律，奖励）驱动运动激活和躁狂谱风险的机制。我们将招募n = 170 一系列终生阈值躁狂症症状，年龄在16至24岁的青少年和年轻人 但是没有BSD的先前历史。参与者将完成2周的基于现场的运动活动监测 伴有腕部动作法，然后对探索性运动行为进行全面的基于实验室的评估， 昼夜节律功能和奖励灵敏度。通过随访，动作学运动活动和临床状况将是 预期每六个月的索引长达3年。我们的主要目标将检验总体假设 这种运动激活是躁狂症状严重程度和进展的行为标记[AIM 1]，并且 昼夜节律和奖励系统的神经生物学失调驱动运动激活[AIM 2]和躁狂症 随着时间的推移症状进展[AIM 3]。我们将使用高维建模方法来识别 多元运动，昼夜节律，奖励谱系预测躁狂症状及其随着时间的流逝进展， 这将为躁狂谱的更全面的生物行为预测模型提供信息。探索性 分析将1）从新颖的反向翻译任务中纳入更细微的运动指标 2）检查我们模型对躁狂症与其他临床结果的特异性。我们的结果有潜力 到1）通过实时，客观的运动活动监测和 2）提供与躁​​狂症相关的昼夜节律和奖励目标 与当前的最佳实践方法相比，可以更有效地减轻或预防躁狂症的干预措施。