2016 — 2020 |
Soehner, Adriane M. |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Vulnerability to Bipolar Disorder in Adolescence: Interactions Among Sleep Variability, Familial Risk, and Reward-Control Processes @ University of Pittsburgh At Pittsburgh
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.
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0.948 |
2021 |
Soehner, Adriane M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Locomotor Activation and Mania Spectrum Risk: Circadian and Reward Mechanisms @ University of Pittsburgh At Pittsburgh
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.
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0.948 |