Vulnerability to Bipolar Disorder in Adolescence: Interactions Among Sleep Variability, Familial Risk, and Reward-Control Processes

项目摘要/摘要 拟议的K01指导研究科学家发展奖的目的是为候选人提供 在发展情感神经科学和睡眠研究方面拥有先进的专业知识。青春期是一个时期 双相情感障碍(BD)的易感性增加，父母BD病史是一个强有力的危险因素。 奖赏加工和认知控制方面的障碍被认为代表了 BD，以及通常在BD之前或与BD同时发生的精神疾病。在青春期，成熟的 支持奖赏-控制过程的神经回路之间的功能联系平行于BD发病率的上升 费率。这些领域的神经行为障碍即使在精神健康的儿童中也能观察到 躁郁症的父母，可能反映了随后的精神病态的脆弱性。以告知更有力的信息 对于BD的预防性治疗，重要的是确定参与这些因素的可修改因素 跨诊断神经行为靶点被认为是BD和相关形式BD风险的基础 精神病理学，特别是高危样本。在大多数形式的精神病理学中，睡眠都会受到干扰。 睡眠模式在青春期变得越来越多变，睡眠是大脑的一个既定贡献者 可塑性和功能性。睡眠变异性增加可能会给双相情感障碍的后代带来更多不良影响 父母，他们的神经回路可能已经受到损害。然而，稳定睡眠是有可能的 可能会保护双相情感父母后代中脆弱的神经回路。 睡眠变异性加剧先前存在的神经行为脆弱性的模型(奖励处理， 与健康青少年相比，双相情感障碍父母的青春期子女的认知控制)。年长的青少年 14-18岁将被招募：30名健康父母(LR)的低风险健康子女和30名高风险健康子女的独特样本 双相父母(HR)的风险后代，通过一系列非BD的存在进一步增加了风险 精神变态学。所有参与者将完成经过充分验证的日常睡眠测量，然后进行功能磁共振成像和 奖赏加工和认知控制的行为测量。对于fMRI，与任务相关的活动和 支持奖赏处理的相互连接的神经回路之间的连接(腹侧额纹状体)和 将评估认知控制(背侧前额叶)。主要目的是评估睡眠的可变性作为预测指标 在奖赏处理(目标1)和认知控制(目标2)的后续神经行为缺陷的HR和 LR.据预测，睡眠和神经行为功能之间的关系将受到群体的调节 状态，这样睡眠变异性将与HR神经行为功能受损更密切相关 相对于LR。探索性目标将测试稳定睡眠变异性的程度(通过简短的行为 操作)在HR组(N=15)的子集中调节这些神经行为测量。短期内 此K01应用程序的目标是应用前瞻性睡眠测量和以睡眠为重点的实验 首先确定并随后参与与BD风险相关的神经行为目标的干预 青少年。长期目标是应用纵向设计和以睡眠为重点的干预(两者 实验和临床)来研究睡眠昼夜节律的神经行为机制 这些过程可能参与了BD情绪调节障碍的过程和治疗。应聘者拥有 在睡眠和昼夜节律测量、行为睡眠干预和情感科学方面的专业知识 方法对成人心境障碍患者进行问卷调查。她寻求建立技能，为她塑造和修改角色做好准备 易感青少年患BD风险的睡眠昼夜节律和神经行为途径。她将获得 通过以下方面的培训获得必要的知识和技能：1)BD神经发育模型；2)高级fMRI 网络分析，以及3)行为睡眠研究与神经成像的结合。培训和 拟议奖项的研究活动将在匹兹堡大学系完成 精神病学，发展情感神经科学、睡眠医学和躁郁症研究的领先中心 精神错乱。这位候选人组建了一支由资深调查人员组成的指导团队，他们拥有出色的跟踪能力 培养初级科学家并支持他们发展成为非常成功的独立科学家的记录 调查人员。导师将提供与应聘者领域相对应的专业知识和培训 目标：精神疾病人群中的情感神经科学和神经影像(菲利普斯)，发展 BD的精神病理学(Birmaher)和行为睡眠医学(Buysse)。政府所提供的资源 匹兹堡大学与导师团队提供的专业知识相结合，有力地定位了 实现她提出的培训、研究和职业目标的候选人。

PROJECT SUMMARY/ABSTRACT The aim of the proposed K01 Mentored Research Scientist Development Award is to provide the candidate with advanced expertise in developmental affective neuroscience and sleep research. Adolescence is a period of heightened vulnerability to bipolar disorder (BD), and parental history of BD is a robust risk factor. Impairments in reward processing and cognitive control are hypothesized to represent core mechanisms of BD, as well as psychiatric conditions that often precede or co-occur with BD. In adolescence, maturation of functional connections among neural circuitry supporting reward-control processes parallel rising BD incidence rates. Neurobehavioral impairments in these domains are observed even in psychiatrically healthy offspring of bipolar parents, perhaps reflecting vulnerabilities to subsequent psychopathology. To inform more potent preventative treatments for BD, it is important to characterize modifiable factors that engage these transdiagnostic neurobehavioral targets hypothesized to underlie risk for BD and related forms of psychopathology, particularly in high-risk samples. Sleep is disturbed across most forms of psychopathology. Sleep patterns become increasingly variable in adolescence, and sleep is an established contributor to brain plasticity and function. Increased sleep variability could confer more adverse effects in offspring of bipolar parents, for whom neural circuitry may already be compromised. However, it is possible that stabilizing sleep may protect vulnerable neural circuitry in offspring of bipolar parents.  The proposed research aims to test a model in which sleep variability exacerbates pre-existing neurobehavioral vulnerabilities (reward processing, cognitive control) in adolescent offspring of bipolar parents relative to healthy adolescents. Adolescents aged 14-18yr will be recruited: 30 low-risk healthy offspring of healthy parents (LR) and a unique sample of 30 high- risk offspring of bipolar parents (HR), further enriched for risk via the presence of a range of non-BD psychopathology. All participants will complete well-validated daily sleep measures followed by fMRI and behavioral measures of reward processing and cognitive control. For fMRI, task-related activity and connectivity among interconnected neural circuits supporting reward processing (ventral frontostriatal) and cognitive control (dorsal prefrontal) will be assessed. The primary aims assess sleep variability as a predictor of subsequent neurobehavioral deficits in reward processing (Aim 1) and cognitive control (Aim 2) in HR and LR. It is predicted that relationships between sleep and neurobehavioral function will be moderated by group status, such that sleep variability will be more strongly related to impaired neurobehavioral function in HR relative to LR. The exploratory aim will test the extent to which stabilizing sleep variability (via a brief behavioral manipulation) modulates these neurobehavioral measures in a subset of the HR group (N=15). The short-term goal of this K01 application is to apply prospective sleep measurement and a sleep-focused experimental intervention to first identify, and subsequently engage, neurobehavioral targets relevant to BD risk in adolescents. The long-term goal is to apply longitudinal designs and sleep-focused interventions (both experimental and clinical) to examine the neurobehavioral mechanisms through which sleep-circadian processes may contribute to the course and treatment of mood dysregulation in BD. The candidate possesses expertise in sleep and circadian rhythm measurement, behavioral sleep intervention, and affective science methods in adult mood disorders. She seeks to build skills that will prepare her to characterize and modify sleep-circadian and neurobehavioral pathways of BD risk in vulnerable adolescents. She will acquire the necessary knowledge and skills through training in: 1) neurodevelopmental models of BD, 2) advanced fMRI network analyses, and 3) the integration of behavioral sleep research with neuroimaging. Training and research activities for the proposed award will be completed at the University of Pittsburgh Department of Psychiatry, a leading center for research on developmental affective neuroscience, sleep medicine, and bipolar disorders. The candidate has assembled a mentorship team of senior investigators who possess stellar track records of training junior scientists, and supporting their development into highly successful independent investigators. Mentors will provide expertise and training in domains that correspond with the candidate's objectives: affective neuroscience and neuroimaging in psychiatric populations (Phillips), developmental psychopathology of BD (Birmaher), and behavioral sleep medicine (Buysse). The resources afforded by the University of Pittsburgh combined with the expertise provided by the mentorship team strongly position the candidate to achieve her proposed training, research, and career goals.