Dean Beebe - US grants

DESCRIPTION (provided by applicant): The candidate, Dean W. Beebe, Ph.D., is an Assistant Professor of Pediatrics at Cincinnati Children's Hospital Medical Center. This K23 application will establish his independent research career in patient-oriented research into the nature, etiology and reversibility of the neurobehavioral effects of pediatric sleep disorders. This will be accomplished through a five-year training program and related research project. The training program has four specific objectives. First, the candidate will build a working knowledge of the biological processes that underlie normal and abnormal sleep in children and adolescents, with a particular focus on the mechanisms by which sleep pathology might cause neurobehavioral symptoms. This will provide an essential background in the physiology and pathophysiology of sleep, coupled with broad exposure to the diagnosis, measurement, and treatment of pediatric sleep disorders. Second, the candidate will enhance his training in longitudinal and epidemiological research design and analysis, with a particular focus on neurobehavioral outcome research. This will provide the skills needed to competently design and execute independent research in this area. Third, the candidate will improve his scientific writing and grant proposal skills. Finally, he will enhance his knowledge of the ethical conduct of clinical research. This training will take place under the guidance of faculty from a leading pediatric department and nearby medical school. The primary sponsor is an established researcher in the neurobehavioral effects of pediatric illness who has a history of successful career mentorship. Co-sponsors represent subspecialty divisions that are directly relevant to the research and career development plan. The proposed research plan focuses on an understudied population that is at high risk for obstructive sleep apnea (OSA): obese teens and preteens. This plan has been designed with two overarching goals: (1) to enhance scientific understanding of the presence, nature, and reversibility of neurobehavioral symptoms of OSA within this population, and (2) to expand the field's understanding of the effects of sleep pathology, broadly defined, on pediatric neurobehavioral functioning. Capitalizing on the unique combination of resources available to the candidate, this project will provide exceptional training in research linking the biological processes of sleep pathology with their neurobehavioral manifestations, while also generating much needed scientific data on a population that is rapidly growing and is at significant risk for both sleep disorders and poor neurobehavioral outcome.

DESCRIPTION (provided by applicant): The candidate, Dean W. Beebe, Ph.D., is an Assistant Professor of Pediatrics at Cincinnati Children's Hospital Medical Center. This K23 application will establish his independent research career in patient-oriented research into the nature, etiology and reversibility of the neurobehavioral effects of pediatric sleep disorders. This will be accomplished through a five-year training program and related research project. The training program has four specific objectives. First, the candidate will build a working knowledge of the biological processes that underlie normal and abnormal sleep in children and adolescents, with a particular focus on the mechanisms by which sleep pathology might cause neurobehavioral symptoms. This will provide an essential background in the physiology and pathophysiology of sleep, coupled with broad exposure to the diagnosis, measurement, and treatment of pediatric sleep disorders. Second, the candidate will enhance his training in longitudinal and epidemiological research design and analysis, with a particular focus on neurobehavioral outcome research. This will provide the skills needed to competently design and execute independent research in this area. Third, the candidate will improve his scientific writing and grant proposal skills. Finally, he will enhance his knowledge of the ethical conduct of clinical research. This training will take place under the guidance of faculty from a leading pediatric department and nearby medical school. The primary sponsor is an established researcher in the neurobehavioral effects of pediatric illness who has a history of successful career mentorship. Co-sponsors represent subspecialty divisions that are directly relevant to the research and career development plan. The proposed research plan focuses on an understudied population that is at high risk for obstructive sleep apnea (OSA): obese teens and preteens. This plan has been designed with two overarching goals: (1) to enhance scientific understanding of the presence, nature, and reversibility of neurobehavioral symptoms of OSA within this population, and (2) to expand the field's understanding of the effects of sleep pathology, broadly defined, on pediatric neurobehavioral functioning. Capitalizing on the unique combination of resources available to the candidate, this project will provide exceptional training in research linking the biological processes of sleep pathology with their neurobehavioral manifestations, while also generating much needed scientific data on a population that is rapidly growing and is at significant risk for both sleep disorders and poor neurobehavioral outcome.

DESCRIPTION (provided by applicant): The candidate, Dean W. Beebe, Ph.D., is an Assistant Professor of Pediatrics at Cincinnati Children's Hospital Medical Center. This K23 application will establish his independent research career in patient-oriented research into the nature, etiology and reversibility of the neurobehavioral effects of pediatric sleep disorders. This will be accomplished through a five-year training program and related research project. The training program has four specific objectives. First, the candidate will build a working knowledge of the biological processes that underlie normal and abnormal sleep in children and adolescents, with a particular focus on the mechanisms by which sleep pathology might cause neurobehavioral symptoms. This will provide an essential background in the physiology and pathophysiology of sleep, coupled with broad exposure to the diagnosis, measurement, and treatment of pediatric sleep disorders. Second, the candidate will enhance his training in longitudinal and epidemiological research design and analysis, with a particular focus on neurobehavioral outcome research. This will provide the skills needed to competently design and execute independent research in this area. Third, the candidate will improve his scientific writing and grant proposal skills. Finally, he will enhance his knowledge of the ethical conduct of clinical research. This training will take place under the guidance of faculty from a leading pediatric department and nearby medical school. The primary sponsor is an established researcher in the neurobehavioral effects of pediatric illness who has a history of successful career mentorship. Co-sponsors represent subspecialty divisions that are directly relevant to the research and career development plan. The proposed research plan focuses on an understudied population that is at high risk for obstructive sleep apnea (OSA): obese teens and preteens. This plan has been designed with two overarching goals: (1) to enhance scientific understanding of the presence, nature, and reversibility of neurobehavioral symptoms of OSA within this population, and (2) to expand the field's understanding of the effects of sleep pathology, broadly defined, on pediatric neurobehavioral functioning. Capitalizing on the unique combination of resources available to the candidate, this project will provide exceptional training in research linking the biological processes of sleep pathology with their neurobehavioral manifestations, while also generating much needed scientific data on a population that is rapidly growing and is at significant risk for both sleep disorders and poor neurobehavioral outcome.

Project Summary/Abstract Millions of US adolescents are chronically sleep-deprived during a developmentally critical period, when the proximal effects of sleep deprivation may have serious long-term consequences. Although inadequate sleep during adolescence has been associated with poor health outcomes, the conclusions that can be drawn from prior studies are limited by their correlational nature. A few experimental studies have shown that sleep- deprived adolescents fall asleep easily, but this accounts for only one of the suspected effects of sleep deprivation on behavior and does not address effects on brain functioning. Experimental studies from other developmental periods have suggested that inadequate sleep alters brain activity and causes behavioral deficits, most prominently inattention. However, findings from young children are too incomplete, relate to demands that are too different, and are based upon a sleep physiology that is too dissimilar, to be extrapolated to adolescents. Similarly, adult findings lack ecological (real world) validity when applied to adolescents and do not take into account developmental factors. The field lacks developmentally-appropriate experimental work that conclusively determines whether and how inadequate sleep alters adolescents' neural and neurobehavioral functioning. This has limited the conclusions one can draw about the effects that chronic sleep restriction has on adolescents and has slowed public health initiatives to improve adolescent sleep. The overall goal of our multidisciplinary research program is to advance science and promote public health by clarifying the proximal and distal effects of inadequate sleep during adolescence. To complement and inform the longitudinal work on distal effects that is underway and planned through our program, the current study will examine the proximal impact of experimental sleep restriction on healthy adolescents' neural and behavioral functioning, focusing on the fundamental neurobehavioral system of sustained attention. 100 adolescents will undergo a within-subjects randomized crossover protocol that includes five nights in a sleep deprivation condition (SD; 6.5 hours in bed with lights out) and five in an healthy duration condition (HD;10 hours with lights out), followed by morning assessments at the end of each week. The central hypothesis is that, relative to the HD condition, adolescents in the SD condition will display attention deficits that will be reflected in direct assessments of neural functioning (EEG and fMRI) and in behavioral measures. This study aims to determine (1) the proximal impact of sleep restriction on adolescents' neurobehavioral functioning, (2) the impact of sleep restriction on adolescents' brain functioning while they are engaged in sustained attention tasks, and (3) the relationship between neural state and neurobehavioral performance in sleep-deprived adolescents. In achieving these aims, this study will determine the impact of chronic sleep restriction on important aspects of the daily functioning of adolescents, and gain new insight into the neural mechanisms that underlie this impact.

DESCRIPTION (provided by applicant): Obesity prevention has become a national health imperative, and may be exceptionally important yet particularly difficult during adolescence. Adolescents develop enduring lifestyle patterns in their dietary choices and activity levels that can set the stage for life-long obesity, so it is essential that the field identify novel modifiabl factors that impact the lifestyle patterns of adolescents. This study tests a promising new target for prevention efforts. Our group has collected pilot data that builds upon prior correlational findings in children and experimental findings in adults to suggest that sleep restriction (SR) causes adolescents to eat more calories without increasing their physical activity. If these pilot findings are confirmed in a larger, more definitive study, obesity prevention efforts could be augmented by strategies to alleviate SR, which is known to be extremely common among adolescents. Further, our pilot findings with adolescents extend prior adult research to suggest that the mechanism for this effect is a particular increase in the reward value of sweet/ dessert foods, causing them to be eaten in greater amounts, to be perceived more positively, and to elicit more activation of reward-related brain regions on fMRI during SR. Confirmation of these pilot findings will inform the complex bio-behavioral foundations of obesity, and identify secondary points of intervention for occasions when an adolescent's sleep is inadequate due to unusual circumstances or to an intractable sleep disorder. However, before such benefits can be realized, the field must overcome significant gaps in our knowledge base. Our pilot studies yielded intriguing findings, but were too small and methodologically limited to be definitive. Othe pediatric findings have come almost exclusively from correlational studies, greatly limiting causal inferences. Adult SR findings also are difficult to apply to adolescents because of multiple methodological and developmental factors. We propose to overcome these limitations with a well-powered mechanistic study that balances experimental rigor with real-world relevance during the high-risk period of adolescence. Healthy, non- obese 14-17 year-olds will undergo a randomized cross-over trial of an experimental sleep manipulation across 5-night periods (simulating a school week), comparing nightly sleep of (a) ~9 hr., the recommendation for healthy sleep vs. (b) ~6.3 hr., which many teens experience on school nights (SR). Lab assessments of teens' perception of, and brain responses to, specific foods will be paired with measures of real-world dietary and activity patterns to definitively test (a) the effect of SR on te caloric intake and activity of healthy adolescents, (b) the effect of SR on the rewarding quality o calorie-dense foods, and (c) the link between changes in caloric intake and the rewarding quality of food. Analyses will further explore whether risk factors for obesity identify which adolescents are especially vulnerable to the effect of SR on caloric intake. Findings will have direct implications for improving obesity prevention and for discoveries into obesity's complex bio-behavioral mechanisms.

Project Summary Despite major public health efforts, auto crashes remain by far the leading cause of death among 16-19 year-olds and are a major cause of non-fatal injuries. There is a clear, ongoing need to identify unaddressed, reversible conditions that increase risk for adolescent drivers. We propose that obstructive sleep apnea (OSA) is an under-recognized, treatable condition that worsens driving skills in adolescents by inducing sleepiness and inattention. Suggestive evidence converges from studies of (a) crash risk in adults with OSA, (b) neurobehavioral functioning in youth with OSA, and (c) neurobehavioral and driving skills in sleep-deprived adolescents. If our hypotheses are correct, documenting and addressing the effect of adolescent OSA on driving skills could improve OSA care and prevent thousands of crash-related injuries and deaths every year. However, evidence remains circumstantial and it is questionable to generalize findings from research on highly-experienced middle-aged adult drivers to inexperienced adolescent drivers, for whom the act of driving places much greater demands on vigilance and divided attention. Our long-term plan is to conduct a detailed on-road study which could definitively speak to the driving-related risk and reversibility of adolescent OSA. Before making that investment of time and resources, we first must clearly show driving skill deficits in a sample of rigorously-diagnosed adolescents with and without OSA in a controlled setting that allows for sensitive measurement of effects and ethical presentation of driving challenges. The proposed small-scale study will accomplish those critical first steps, while also providing key guidance on likely mechanisms of effect. Thirty 16-19-year-old drivers with untreated OSA and thirty OSA-free controls will undergo driving simulation of a nature that is sensitive to OSA in adults and to sleep restriction in teens. Our first aim is to test whether adolescent OSA increases driving risk. Compared to controls, we expect that that adolescents with OSA will have more difficulty maintaining their lanes in the simulator, as well as more protracted eye glances from the roadway when engaged in a text messaging conversation. Our second aim is to test whether inattention and daytime sleepiness are key mechanism in inducing OSA-linked driving risk. This novel study will be the first to test the presence and mechanisms underlying driving skill deficits in youth with OSA. It capitalizes on the unique equipment available at Cincinnati Children's and the unique expertise of our research team, which includes experts in adolescent sleep pathology, neurobehavioral assessment, adolescent attention, driving simulation, statistical analyses, and generalization to real-world driving settings. While quite treatable, adolescent OSA is rarely detected, let alone treated. If our hypotheses are correct, this study will open new opportunities to improve the health and safety of young drivers with currently undetected OSA, as well as the millions more with whom they share the road.

Project Summary Recent research shows that sleep could play a novel role in preventing obesity and long-term morbidity. Population studies find that too little sleep predicts the development of obesity and experimental studies show that short sleep increases dietary intake without increasing physical activity. Sleep may be a particularly potent intervention target for adolescents. During adolescence, inadequate sleep is very common, obesity rates are rising most, non-sleep-oriented obesity prevention programs have had least success, and young people can develop enduring dietary patterns that set the stage for life-long obesity and health risk. Our lab has shown both the promise of longer sleep for adolescents and a critical knowledge gap. We found that extending adolescents? sleep via earlier bedtimes impressively reduced caloric intake for early chronotypes (?Morning Larks?; who prefer early bed- and rise times), but not late chronotypes (?Night Owls?; who prefer late bed- and rise times). The effect was not only statistically strong, but at roughly 400 calories difference per day, could add up to major shifts in body weight over time. Beyond calorie counts, there was a similar discrepancy in the glycemic load consumed by Larks and Owls after sleep extension, and glycemic load has been independently linked to long-term morbidity. We assert that the discrepancy in how Larks and Owls responded to longer sleep is due to circadian misalignment: a mismatch between the timing of external sleep-wake demands and internal biological clock. We propose that, for adolescent Owls, an early-to-bed intervention induces misaligned sleep timing that counters the benefits of longer sleep duration. In adults, severe circadian misalignment dramatically increases the risk for obesity, and even modest misalignment is linked to higher caloric intake. If a cause-effect relationship holds in adolescence, common sleep advice emphasizing earlier bedtimes might waste limited resources or even do harm for Owls. In contrast, an approach that considers chronotype might capitalize on the potent effect of improved sleep that we have shown for Larks. Here, we propose a novel experimental study in which 124 healthy 14- 18-year-olds (62 Owls and 62 Larks) complete a 3-week trial involving periods of sleep restriction and sleep extension, in which the extension periods are randomly assigned to be aligned vs. misaligned relative to chronotype. Focusing independently on caloric intake and glycemic load, we will assess the dietary effect of sleep extension when it is well-timed versus poorly-timed relative to adolescents? internal clocks. We will test a causal model in which sleep timing plays an important role in promoting or negating the benefits of sleep extension. This is pivotal next step for our research program, which has shown the promise of sleep extension to prevent obesity and morbidity, but so far only for early chronotypes (Larks). At the end of this study, we anticipate having the knowledge needed to better harness the power of sleep to prevent obesity and long-term morbidity for at-risk youth, laying the foundation for more effective public health interventions.