Brant P. Hasler, Ph.D. - US grants

DESCRIPTION (provided by applicant): The candidate's long-term goal is to develop an independent research program investigating the role of circadian rhythm disturbance and impaired reward function as mechanisms of vulnerability to substance use disorders (SUDs). Evidence suggests that circadian rhythms may play a key role in substance use (SU), specifically via interactions with the reward system. However, human studies have not yet examined the precise underlying mechanisms of these relationships. Thus, two priorities are (1) investigating the neurobehavioral underpinnings of circadian-reward interactions, and (2) clarifying how these circadian-reward mechanisms may contribute to SUD risk. Adolescence is a key developmental stage in which to investigate these mechanisms, as it is a period of marked changes in circadian rhythms, reward function, and initiation of SU. Studying the neurobehavioral mechanisms by which circadian rhythms modulate reward functioning may lead to a better understanding of the etiology of adolescent SU and inform prevention and treatment efforts. The candidate has a strong background in circadian and sleep research, and needs additional training to develop mastery in SU research and neuroimaging methods. The proposed K01 Mentored Research Scientist Development Award would ensure the candidate's successful transition to an independent investigator by providing conceptual and methodological training in three key areas: (1) expertise in adolescent SU from a developmental perspective, (2) expertise in the neurobiology of SU with particular focus on models of altered reward function, and (3) expertise in fMRI methodology, analysis, and interpretation. These training aims are well-matched to the proposed research plan, which aims to investigate the neurobehavioral underpinnings of circadian-reward interactions, and to explore whether circadian-reward mechanisms contribute to risk for SUDs. These goals align with NIDA's 2010 Prevention Objectives of elucidating the neural circuitry underlying addiction, and clarifying how environment and development influence risk and protective factors for SUDs. The proposed research will investigate an adolescent sample in cross-sectional and experimental studies, using a novel within-person design and fMRI to probe the role of circadian rhythms in reward-related brain function. The aims are: (1) to assess cross-sectional associations between SU, SUD risk, and self-reported circadian-sleep timing; (2) to assess diurnal variation in reward-related brain activation; (3) to examine the effects of experimentally-induced, ecologically-valid circadian misalignment on reward-related brain activation; and (4) to gather preliminary data on whether misalignment-associated changes in reward-related brain activation are related to SUD vulnerability. The proposed K01 award will integrate the candidate's previous experience and new skill areas, thus providing him with a solid foundation to launch an innovative, independent research program aimed at investigating the neurobehavioral mechanisms linking SU, reward function, and circadian rhythms, with the ultimate goal of translating identified mechanisms into novel interventions.

DESCRIPTION (provided by applicant): A variety of evidence suggests that sleep, circadian rhythms, and circadian alignment influence the development of alcohol use disorders (AUDs) during adolescence and young adulthood. This pathway is likely bidirectional, given that alcohol use (AU) can disrupt sleep and circadian rhythms. However, the precise mechanisms underlying the relationships between sleep/circadian function and AU remain unknown, and thus are the focus of this application. Specifically, we hypothesize that adolescent sleep and circadian disturbances result in dysregulated reward function (i.e., diminished regulatory control, increased sensation seeking, and/or reduced positive affect), which in turn leads to increased AU. Our proposed study will examine the short-term causal dynamics between sleep/circadian factors, reward function, and AU, thereby informing the development of novel prevention and intervention approaches for AUDs. In particular, we propose a prospective, mixed-methods approach in a sample of 32 late adolescents reporting a range of current AU. The novel design combines state-of-the-art in vivo methods (to enhance ecological validity and precision, while limiting recall bias) and laboratory methods (to enhance scientific rigor). Specifically, we will collect (1) 14 days of ecological momentary assessment (self-reported affect, urges, and AU), (2) objective measurements of sleep and endogenous circadian timing (actigraphy, salivary melatonin), and (3) fMRI measures of reward circuitry function. Our design capitalizes on the natural experiment of weekday-weekend changes in sleep, circadian rhythms, and AU, further enhancing validity. We will collect data from all three domains both pre- and post-weekend, enabling us to examine whether sleep, circadian phase, or circadian alignment prospectively predict AU over the short term, and vice versa. The pre- and post-weekend fMRI scans will allow us to evaluate the neural correlates of reward function as an intervening variable between sleep/circadian factors and AU. Specific Aim 1 is to examine whether weekday sleep/circadian factors predict self-reported positive affect, craving, and AU on the weekend under naturalistic conditions. Specific Aim 2 is to examine the dynamic associations between sleep/circadian factors, AU, and neural processing of reward over the weekday-weekend transition. Specific Aim 3 is to examine whether later circadian timing (greater eveningness) confers vulnerability to problematic interactions between sleep/circadian factors and AU. This proposal, in response to PA-12-178 (NIAAA), aims to advance our understanding of the dynamic interactions between sleep/circadian function and alcohol use (AU) during adolescence. This novel study will demonstrate feasibility, help refine our methods, and provide preliminary data for a subsequent larger grant. Together, this preliminary study and the subsequent R01 will have substantial impact and public health significance, with the potential to elucidate novel mechanisms of AU problems at a key developmental stage.

PROJECT SUMMARY A variety of evidence suggests that sleep and circadian rhythms influence the development of alcohol use disorders (AUDs) during adolescence. However, the precise mechanisms underlying the relationships between sleep/circadian function and AU remain unknown, and thus are the focus of this application. Specifically, we hypothesize that adolescent sleep and circadian disturbances result in dysregulated reward function (i.e., diminished impulse control and increased reward sensitivity), which in turn leads to increased AU. Our proposed study will examine the short-term causal dynamics between sleep/circadian factors, reward function, and AU, thereby informing the development of novel prevention and intervention approaches for AUDs. In particular, we propose a prospective, mixed-methods approach in a sample of 150 12th grade (17-19 y/o) students reporting weekly AU. The novel design combines state-of-the-art in vivo methods (to enhance ecological validity and precision, while limiting recall bias) and laboratory methods (to enhance scientific rigor). Specifically, we will collect (1) 8 days of ecological momentary assessment (self-reported craving and AU), (2) objective measurements of sleep and endogenous circadian timing (actigraphy, salivary melatonin, clock gene expression), and (3) objective measures (behavioral and fMRI) of reward function. We will also assess self- reported sleep/circadian factors, reward function, and AU at 3- and 6-month follow-ups, allowing us to examine both proximal and longitudinal associations between our key constructs of interest. Our design capitalizes on the ?natural experiment? of weekday-weekend changes in sleep, circadian rhythms, and AU. Assessing sleep/circadian factors both pre- and post-weekend will enable us to examine whether circadian alignment and/or sleep duration prospectively predict weekend AU, and vice versa. Including pre-weekend behavioral and fMRI tasks will allow us to evaluate objective measures of reward function as intervening variables between sleep/circadian factors and AU. Specific Aim 1 is to establish the extent of proximal prospective associations between sleep/circadian factors, reward function, and AU. Specific Aim 2 is to establish the extent of distal associations between sleep/circadian factors, reward function, and AU. This innovative proposal will rigorously test our novel conceptual model proposing a circadian-reward path to adolescent AUD and examining both proximal and more distal timeframes. It will have substantial impact and public health significance, with the potential to elucidate novel mechanisms of AU problems at a key developmental stage. Demonstration of a sleep/circadian influence on AU would provide scientific justification for testing empirically-supported sleep/circadian interventions to AUD prevention.

PROJECT SUMMARY Substance use disorders (SUDs) often begin during adolescence. Mounting evidence indicates that delayed sleep phase (DSP) may confer risk for adolescent substance use (SU) and SUDs. However, the exact nature of this link and the mechanisms underlying it remain unclear. Circadian misalignment, a mismatch between late sleep hours and early school start times, is a compelling potential contributor to elevated SU in adolescent DSP with plausible neurobehavioral mechanisms. We hypothesize that DSP-associated circadian misalignment decreases impulse control and increases reward sensitivity, thereby increasing SUD risk. The proposed study will, for the first time, (1) comprehensively characterize the SUD risk profile associated with adolescent DSP, and (2) probe whether SUD risk is diminished by altering sleep/circadian timing. The study will assess both established markers of SUD risk and putative neurobehavioral mechanisms (impulsivity and reward sensitivity). Specifically, we propose a comprehensive, multi-method approach to examining DSP?s role in SUD risk, combining laboratory, experimental, and longitudinal studies. We will recruit a sample of 150 twelfth graders (17-19 y/o), divided between 100 DSP and 50 normal phase teens. We will focus on cannabis and alcohol use given their prevalent use in adolescents and evident links to DSP. The lab study compares a group of DSP adolescents to a group of normal phase adolescents on behavioral and neuroimaging (fMRI) tasks tapping impulsivity and reward sensitivity, as well as a circadian phase assessment. In the experimental study, we will probe whether stabilizing circadian phase in the DSP group by using sleep scheduling and chronotherapeutic approaches (e.g., bright light) improves sleep and neurobehavioral function relevant to SUD risk. Finally, we include repeated monthly follow-up assessments of sleep and SU to explore longitudinal associations during the high-risk transition to young adulthood. Aim 1 (Laboratory Study) is to compare a DSP group to a normal phase group on sleep/circadian factors, neurobehavioral markers, and SU. Aim 2 (Experimental Study) is to probe the impact of a sleep phase-stabilizing manipulation on sleep and circadian rhythms, as well as neurobehavioral markers of SUD risk. An Exploratory Longitudinal Aim is to!examine the prospective relationships between DSP characteristics and changes in SU via repeated monthly assessments during the high-risk transition to young adulthood. The proposed study is significant: it focuses a biologically- plausible and modifiable sleep phenotype of particular promise, during a developmental period when the mismatch between DSP and school-imposed early start times is at its worst and overall SUD risk is spiking. The proposed study is innovative: (1) it examines several promising neurobehavioral pathways to adolescent SUD, (2) it combines comprehensive and objective measures of relevant constructs, and (3) it includes an experimental manipulation to probe the mechanisms linking DSP to SUD. Finally, the proposed study will have substantial impact: it may open up novel sleep/circadian-based avenues for prevention and treatment of SUD. !

PROJECT SUMMARY Significance: Sleep disturbances are related to increased alcohol use (AU) and alcohol problems. The mechanisms that account for this association are not well understood. The proposed study will be the first to examine an integrative model including both a positive reinforcement pathway (i.e., higher impulsivity and increased sensitivity to the stimulating effects of alcohol) and a negative reinforcement pathway (i.e., higher anxiety and increased sensitivity to the anxiolytic effects of alcohol) that may link sleep disturbances and alcohol problems. We will use a rigorous multi-method approach that extends the laboratory into the real world. Results may directly inform AU treatment by identifying which specific sleep factors contribute to risk and why. Aims: For the positive reinforcement pathway, we hypothesize that later sleep timing and shorter sleep duration will predict higher impulsivity and greater increases in impulsivity and stimulation while intoxicated. For the negative reinforcement pathway, we hypothesize that lower sleep efficiency, a marker of insomnia, will predict higher anxiety while sober and increased anxiolytic response to alcohol. These processes will account for the association between sleep factors and concurrent and prospective AU outcomes. Specificity of the positive and negative reinforcement pathways will be examined. We will also explore if sex or diagnostic status (alcohol use disorder (AUD), sleep disorders) moderate the relationships between sleep characteristics and reinforcement pathways to AU. Approach: Young adult drinkers (21-30 years of age; 50% female; N = 150) will complete a protocol that includes ecological momentary assessments (EMA), laboratory sleep and alcohol response assessments, and 6-month follow-up. Participants will be current heavy episodic drinkers (i.e., 5+ days in past 30 days of consuming 5+/4+ for males/females; SAMHSA) to ensure sufficient range in alcohol outcomes of interest. We will use two 10-day EMA/actigraphy protocols to track daily sleep characteristics (timing, duration, and efficiency), anxiety, AU (freq. of 5+/4+ drinks/occasion), impulsivity, and subjective alcohol response in the real world. Each EMA protocol will conclude with an overnight sleep laboratory assessment followed by a within-subjects laboratory alcohol administration (counterbalanced: placebo/alcohol sessions) to examine alcohol response. During the chronobiology lab visits, we will use salivary DLMO to assess physiological circadian timing. During the alcohol lab visits, we will measure positive and negative reinforcement pathways via subjective response (stimulation/anxiety) and impulsivity (self-report, tasks). A 90- day timeline follow-back interview delivered 6 months later will allow for the prospective examination of associations between sleep characteristics and later AU (freq. of 5+/4+ drinks/occasion) and problems. The proposed study will provide novel information about how sleep disturbances, a set of modifiable factors, affect alcohol response and impulsivity. These findings may directly translate to prevention/treatment efforts for AUD.

PROJECT SUMMARY Substance Use (SU) and substance use disorders (SUDs) are widely prevalent and pose devastating health, financial and societal costs. The primary goal of the CARRS Center is to understand how sleep and circadian rhythm traits and environmental disruptions during adolescence lead to increased vulnerability for substance abuse. We further aim to test whether manipulation of sleep and circadian factors during adolescence will alter factors associated with increased risk for SU. The incidence of SU and SUDs increases across adolescence, making this sensitive developmental period one of both heightened risk?and heightened opportunity for prevention and intervention. However, to develop effective interventions, we need to identify novel and modifiable risk factors and mechanisms for SUD. Project 2 (P2) of CARRS will test the hypothesis that individual differences in sleep and circadian characteristics during adolescence are associated with self-report, behavioral, and neural indicators of reward function and cognitive control, which in turn are associated with increased risk for SU. Further, P2 tests an experimental intervention that manipulates sleep and circadian rhythms to directly examine its impact on reward function. P2 will study 150 adolescents (age 13?15) with early (n=50) and late (n=100) sleep timing. All participants will complete 2 weeks of home sleep monitoring, followed by an overnight laboratory visit to assess self-report, behavioral, and neuroimaging (fMRI) tasks of cognitive control and reward function, as well as circadian phase via salivary melatonin and molecular rhythms via hair follicles. The Late group will continue to the experimental study, each participant randomized to 2-week manipulation or attentional control conditions (n=50 each). Finally, we include repeated 6-month follow-up assessments of sleep and SU for all participants in P1 and P2 to examine longitudinal associations. Aim 1 is to compare Early versus Late sleepers on sleep/circadian factors and neurobehavioral markers. Dependent variables include circadian phase, sleep duration, and circadian misalignment, as well as self-report, behavioral, and neural measures of cognitive control and reward function. Aim 2 is to probe the acute effects of experimental sleep advance and extension on sleep and circadian rhythms, as well as effects on neurobehavioral markers of SUD risk, in adolescents with late sleep timing (n=100). Our Collaborative Aim (P1/P2) is to examine whether sleep/circadian factors, cognitive control, and reward function predict subsequent SU across follow-up using self-report, behavioral, and neural measures, as well multivariable machine learning approaches (Core C). P2 will draw directly on resources of Core A: Administration, Core B: Phenotyping and Biobanking, and Core C: Data Management and Statistics. Findings from P2 will complement findings on circadian rhythmicity and homeostatic sleep drive from P1 and will provide definitive findings on how manipulation of sleep/circadian rhythms alters cognitive control, reward function, and SU risk in humans, which may, in turn, inform novel sleep and circadian-based interventions to reduce this risk.