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

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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.