David W. Carley - US grants

It has been hypothesized that interactions between state of consciousness and respiratory control variables may be significant in the etiology of periodic breathing (PB) under such conditions as; sleep onset, prematurity, hypoxia, and occlusive sleep apnea (OSA). Because current clinical methods of sleep staging are inadequate to investigate these interactions, a new method, based on spectrum analysis of the electroencephalogram (EEG), is presented for quantifying graded state changes which may occur in conjunction with periodic breathing. Two state indexes are described; Sia, a measure of EEG amplitude and Slf, a measure of the EEG frequency distribution. Broadly speaking, the objective of the proposed work is to is to develop a system by which to study the mechanisms of interaction between state of consciousness and respiration. A related long range goal is to quantitatively evaluate the role of fluctuating state of consciousness in the mechanisms of sleep related apneas. The proposed work is directly related the pathophysiology of OSA and may have implications for the diagnosis and evaluation of therapeutic interventions in this, and other respiratory disorders. The first specific aim of these studies is to critically evaluate the nature and consistency of the relationships between sleep onset and the development of apnea and between relative arousal and the restoration of ventilation in habitual snorers with PB, patients with Cheyne-Stokes respiration (CSR) and patients with OSA. The second specific aim is to assess the role of state of consciousness, and transient changes in state of consciousness, in determining the type and duration of apnea in PB, CSR and OSA. The third specific aim is to quantitatively evaluate potential mechanisms by which changing state of consciousness affects genesis and resolution of sleep-related upper airway occlusion through its influence on respiratory and upper airway muscles activities, inspiratory pressure generation, thoraco-abdominal configuration and arterial blood gases. Subjects for these studies will be patients with OSA , patients with Cheyne-Stokes respiration, and habitual snorers. The specific aims will be met by performing nocturnal polysomnography in all subjects, with standard clinical monitoring augmented to include; a naso-gastric catheter instrumented for diaphragmatic pressure and EMG (EMGdi), fine wire electrodes inserted per-orally to record genioglossus EMG (EMGge), calibrated compartmental ventilation, expired gases and arterial oxygen saturation (SaO2)- For each study Sla and Slf will be computer scored to identify all "transient state changes" (TSC); and airflow, thoraco-abdominal motion and PETCO(2) will be computer-scored to identify and classify all apneas as central, mixed or obstructive. Hypotheses related to the first aim will be tested by computing the concordance between TA's and apneas, stratified by apnea type; and by numerically correlating the relative timing of TA's with apneas as well as the variability of this timing. Hypotheses related to the second and third aims will be tested by performing coherence analysis between the state indexes and each respiratory variable and by multiple regression analysis of respiratory and state variables on apnea type and timing. In addition, interventions including transient closed-system rebreathing and mechanical airway occlusion will be employed to stimulate the effects of occlusive apnea in an attempt to differentiate the importance of various afferent pathways in the stimulation of arousal and of apnea resolution.

It has been hypothesized that interactions between state of consciousness and respiratory control variables may be significant in the etiology of periodic breathing (PB) under such conditions as; sleep onset, prematurity, hypoxia, and occlusive sleep apnea (OSA). Because current clinical methods of sleep staging are inadequate to investigate these interactions, a new method, based on spectrum analysis of the electroencephalogram (EEG), is presented for quantifying graded state changes which may occur in conjunction with periodic breathing. Two state indexes are described; Sia, a measure of EEG amplitude and Slf, a measure of the EEG frequency distribution. Broadly speaking, the objective of the proposed work is to is to develop a system by which to study the mechanisms of interaction between state of consciousness and respiration. A related long range goal is to quantitatively evaluate the role of fluctuating state of consciousness in the mechanisms of sleep related apneas. The proposed work is directly related the pathophysiology of OSA and may have implications for the diagnosis and evaluation of therapeutic interventions in this, and other respiratory disorders. The first specific aim of these studies is to critically evaluate the nature and consistency of the relationships between sleep onset and the development of apnea and between relative arousal and the restoration of ventilation in habitual snorers with PB, patients with Cheyne-Stokes respiration (CSR) and patients with OSA. The second specific aim is to assess the role of state of consciousness, and transient changes in state of consciousness, in determining the type and duration of apnea in PB, CSR and OSA. The third specific aim is to quantitatively evaluate potential mechanisms by which changing state of consciousness affects genesis and resolution of sleep-related upper airway occlusion through its influence on respiratory and upper airway muscles activities, inspiratory pressure generation, thoraco-abdominal configuration and arterial blood gases. Subjects for these studies will be patients with OSA , patients with Cheyne-Stokes respiration, and habitual snorers. The specific aims will be met by performing nocturnal polysomnography in all subjects, with standard clinical monitoring augmented to include; a naso-gastric catheter instrumented for diaphragmatic pressure and EMG (EMGdi), fine wire electrodes inserted per-orally to record genioglossus EMG (EMGge), calibrated compartmental ventilation, expired gases and arterial oxygen saturation (SaO2)- For each study Sla and Slf will be computer scored to identify all "transient state changes" (TSC); and airflow, thoraco-abdominal motion and PETCO(2) will be computer-scored to identify and classify all apneas as central, mixed or obstructive. Hypotheses related to the first aim will be tested by computing the concordance between TA's and apneas, stratified by apnea type; and by numerically correlating the relative timing of TA's with apneas as well as the variability of this timing. Hypotheses related to the second and third aims will be tested by performing coherence analysis between the state indexes and each respiratory variable and by multiple regression analysis of respiratory and state variables on apnea type and timing. In addition, interventions including transient closed-system rebreathing and mechanical airway occlusion will be employed to stimulate the effects of occlusive apnea in an attempt to differentiate the importance of various afferent pathways in the stimulation of arousal and of apnea resolution.

It has been hypothesized that interactions between state of consciousness and respiratory control variables may be significant in the etiology of periodic breathing (PB) under such conditions as; sleep onset, prematurity, hypoxia, and occlusive sleep apnea (OSA). Because current clinical methods of sleep staging are inadequate to investigate these interactions, a new method, based on spectrum analysis of the electroencephalogram (EEG), is presented for quantifying graded state changes which may occur in conjunction with periodic breathing. Two state indexes are described; Sia, a measure of EEG amplitude and Slf, a measure of the EEG frequency distribution. Broadly speaking, the objective of the proposed work is to is to develop a system by which to study the mechanisms of interaction between state of consciousness and respiration. A related long range goal is to quantitatively evaluate the role of fluctuating state of consciousness in the mechanisms of sleep related apneas. The proposed work is directly related the pathophysiology of OSA and may have implications for the diagnosis and evaluation of therapeutic interventions in this, and other respiratory disorders. The first specific aim of these studies is to critically evaluate the nature and consistency of the relationships between sleep onset and the development of apnea and between relative arousal and the restoration of ventilation in habitual snorers with PB, patients with Cheyne-Stokes respiration (CSR) and patients with OSA. The second specific aim is to assess the role of state of consciousness, and transient changes in state of consciousness, in determining the type and duration of apnea in PB, CSR and OSA. The third specific aim is to quantitatively evaluate potential mechanisms by which changing state of consciousness affects genesis and resolution of sleep-related upper airway occlusion through its influence on respiratory and upper airway muscles activities, inspiratory pressure generation, thoraco-abdominal configuration and arterial blood gases. Subjects for these studies will be patients with OSA , patients with Cheyne-Stokes respiration, and habitual snorers. The specific aims will be met by performing nocturnal polysomnography in all subjects, with standard clinical monitoring augmented to include; a naso-gastric catheter instrumented for diaphragmatic pressure and EMG (EMGdi), fine wire electrodes inserted per-orally to record genioglossus EMG (EMGge), calibrated compartmental ventilation, expired gases and arterial oxygen saturation (SaO2)- For each study Sla and Slf will be computer scored to identify all "transient state changes" (TSC); and airflow, thoraco-abdominal motion and PETCO(2) will be computer-scored to identify and classify all apneas as central, mixed or obstructive. Hypotheses related to the first aim will be tested by computing the concordance between TA's and apneas, stratified by apnea type; and by numerically correlating the relative timing of TA's with apneas as well as the variability of this timing. Hypotheses related to the second and third aims will be tested by performing coherence analysis between the state indexes and each respiratory variable and by multiple regression analysis of respiratory and state variables on apnea type and timing. In addition, interventions including transient closed-system rebreathing and mechanical airway occlusion will be employed to stimulate the effects of occlusive apnea in an attempt to differentiate the importance of various afferent pathways in the stimulation of arousal and of apnea resolution.

Sleep apnea syndrome affects at least 3% - 5% of the adult population in this country and significant morbidity or even mortality can result from this disorder. It is now well established that the prevalence of sleep-related apnea is dramatically elevated in the elderly with recent estimates ranging from 28% - 67% for elderly males and from 20% - 54% for elderly females. Additional epidemiological data demonstrate strong associations of sleep apnea with hypertension and obesity, and suggest that sleep-related apnea may be an independent risk factor for cardiovascular morbidity and mortality. Despite these facts, the mechanisms of apnea genesis remain poorly understood. This uncertainty stems in part from the lack of an appropriate animal model by which apneas may be studied in all stages of sleep. We have recently extended the work of others to characterize a rat model of physiological apnea, demonstrating that rats of various strains, including obese, hypertensive, pigmented and albino rats, express spontaneous apnea at rates of 3 - 10 and 10 - 30 per hour of nonrapid eye movement and rapid eye movement sleep, respectively. We have collected preliminary data which indicate that: 1) apnea expression increases robust1y as individual rats age from 3 months to 12 months and 2) in comparison to 3 month old rats, apnea indexes are higher in groups of 17 and 26 months old rats; thus suggesting that the rat may serve as a valuable animal model of the age-related increase in sleep apnea. In this pilot study we will measure sleep-related respiratory and cardiovascular behaviors longitudinally in multiple age-cohorts of Sprague-Dawley rats, the strain for which apnea expression has been best characterized in young adults. These protocols will clearly determine any age-related changes in apnea expression as well as the sleep state dependencies of this effecL Correlated changes in chemoreflexes and baroreflexes during sleep will also be identified. At the conclusion of this one year program, the feasibility of using the rat as an animal model of sleep apnea in aging should be clearly demonstrated. If positive, these findings will constitute the core of preliminary work necessary for a competitive R01 application to either the NIA or the NHBLI focused on identifying the mechanisms underlying age-related changes in apnea expression in the rat.

Respiratory pattern generation and motor output integration are strongly influenced by behavioral state. In particular, rapid eye movement (REM) sleep is associated with increased variability of respiratory timing and effort. In extreme cases, the respiratory dysrhythmia permitted or provoked during REM sleep appears to be a pathogenic factor for sleep-related breathing disorders such as sleep apnea syndrome. The neuronal networks and synaptic mechanisms that render respiratory outputs more labile during REM sleep remain poorly defined, but during the first funding cycle of this research program we developed key evidence supporting a discrete respiratory modulating region (RMR) within the pedunculopontinetegmental (PPT) nucleus of the pons. The PPT also is an important region for REM sleep homeostasis. We showed that PPT stimulation produced respiratory dysrhythmia in sleeping and anesthetized animals and this application presents preliminary evidence that PPT lesions reduce apnea expression during REM sleep. During years 6 to 10 we will pursue 3 specific aims to determine the anatomical localization, synaptic regulation, and physiological relevance of neurons in the RMR for state-dependent control of respiratory pattern variability. Aim 1 will employ nanoliter injections of glutamate and polygraphic monitoring to test the hypothesis that the RMR is anatomically distinct from regions within the PPT responsible for regulation of REM sleep and associated phenomena, including: EEG activation, hippocampal theta rhythm, and ponto-geniculo-occipital wave generation. Aim 2 will test the hypothesis that making excitotoxic lesions to the functionally identified RMR will decrease respiratory variability during sleep, and in particular during REM sleep. Defining the characteristic extent of the RMR in Aim 1 will help us to tune the size of these lesions, and we will correlate the extent of cell loss with the respiratory impact. Aim 3 will use injections of agonists and antagonists of, and immunohistochemistry for specific glutamate receptor subtypes to define the synaptic regulation of RMR neurons by glutamate. Extending the progress of the first funding cycle, these aims will provide important insights regarding the state-dependent mechanisms by which the PPT modulates respiratory pattern.

DESCRIPTION (provided by applicant): The broad goal of this application is to create and nurture the early development of an interdisciplinary team that will broaden the research scope and accelerate the pace of discovery into the impact of sleep on alertness and cognitive/motor performance. A related goal will be to enable development of new analytical methods to deepen insight into the basic mechanisms linking sleep to alertness and cognitive/motor function. The potential impact of defining these poorly understood mechanisms is great. Less than one-quarter of the population routinely achieves an optimal amount of sleep. Insufficient or disordered sleep reduces quality of life and worker and student performance;impairs mood, judgment, alertness, and cognitive/motor performance;and increases the risk of accidents. Further, the prevalence and consequences of insufficient or poor sleep differ among men and women, different races/ethnicities, and across age groups. Defining how sleep influences alertness and cognitive/motor performance, and how this may differ among key subgroups or between individuals, is of great significance to the promotion of optimal health and well-being. At UIC, we have an ideal opportunity to address this unmet research need by building a cohesive research team representing: nursing and sleep sciences;psychological and physiological sciences;biological and social sciences;and mathematics and engineering. Specifically, we will accomplish the following: AIM 1 is to institute the team and develop shared terminology around key research concepts and methods. The initial vehicle will be a dedicated research retreat. Two key focus areas illustrate the need for and benefits of interdisciplinary formation: 1) bridging basic animal science to human investigation and 2) developing new mathematical and imaging methods to understand group differences and to predict individual variations in the impact of sleep on daytime function. AIM 2 is to develop a shared conceptual framework representing cutting edge thinking spanning the represented disciplines. A central activity to achieve this goal will be bi-weekly seminars structured to facilitate sharing key research findings and interpretive concepts in a highly interactive and supportive environment. Consultants also will support this team effort. AIM 3 is to develop a specific and practical team research agenda. During a second research retreat the team will outline the shape and scope of a realistic research agenda. During year 2, working subgroups will draft and continue to refine sections of the research agenda, prior to team approval and final review by and endorsement by campus administration. Accomplishing these specific aims will strongly position the team to enter its developmental stage, during which multiple research project grants will be submitted. We anticipate the generation of multiple R21, R01 or P01 applications from the team. The team's innovative focus on bridging animal to human investigation, to exploring the basis for group and individual differences in the relationships between sleep, alertness and behavior, and to developing novel mathematical and imaging methods will serve as a model to other teams. PUBLIC HEALTH RELEVANCE: The proposed activities will create and nurture the early development of a new interdisciplinary team. The long- term aim of this team will be to elucidate the basic mechanisms linking sleep, alertness and cognitive/motor performance. Our team will encompass numerous traditional disciplines that do not historically collaborate actively, enabling us to bridge animal investigation to human behavior and to develop new mathematical models, analytical methods and imaging tools to understand how the impact of sleep on alertness and cognitive/motor performance may differ according developmental status, age, gender, race/ethnicity and health status, and even to predict differences between individuals.

Sleep related breathing disorders (SRBD), especially obstructive sleep apnea (OSA), represent an important health problem, conferring substantial cognitive/behavioral symptoms and increased risk of motor vehicle accident, hypertension, myocardial infarction, stroke, diabetes and death on at least 3% of the US population. Identifying novel treatments for OSA would be of great public health significance, because fully effective and acceptable OSA treatments are lacking. A critical need remains for NIH supported, mechanistically driven proof-of-concept clinical studies to evaluate novel therapeutic strategies. Despite basic research advances regarding the pathogenesis of OSA, generally effective drug treatments have not been identified. Based on our animal and preliminary human data, we propose to test the innovative hypothesis that cannabimimetic drugs are both effective in reducing sleep apnea severity and disease modifying in protecting against cardiovascular and neurological sequelae of OSA. Project 1 will be a randomized, placebo-controlled parallel groups proof-of-concept clinical trial of dronabinol in patients with OSA. Subjects will be randomized to receive either placebo or dronabinol for a period of 6 weeks. The overarching goal will be to establish the safety, tolerability and therapeutic efficacy of dronabinol in OSA, with co-primary efficacy endpoints including: reduction in apnea/hypopnea index (AHI) and improved subjective and objective daytime alertness at the end of treatment. Secondary endpoints will include improved oxygenation, sleep quality, blood pressure control and time-on-treatments effects. Project 2 will employ anesthetized and chronically instrumented conscious behaving animals to directly test the mechanisms of dronabinol action schematized in figure 1. For example, we will characterize dronabinol's dose-dependent inhibition of afferent vagal reflexes elicited by pharmacological and mechanical stimuli. We will use CB1 and CB2 antagonists to confirm the receptor targets for reduced apnea propensity and we will establish the CNS versus vagal-reflex impact of dronabinol on upper airway muscle activity during sleep. We will test the hypothesis that cannabimimetics lower blood pressure by reducing sympathetic activity. Taken together, these projects will provide critical evidence regarding the potential efficacy and mechanisms of action for cannabimimetic treatment of OSA. By providing a path toward the first viable OSA pharmacotherapeutic, the proposed studies could have a tremendous impact on clinical practice.