This is a revised application of MH024652, originally reviewed in October, 2006. Primary Insomnia (PI) is a prevalent and chronic health problem associated with substantial morbidity, including increased risk for mood disorders. Despite its prevalence and consequences, little is known about insomnia pathophysiology. In this revised competing continuation, we will build on three novel findings from the current funding period: 1) Using ecological momentary assessment (EMA), we have identified a distinctive diurnal pattern of mood and arousal symptoms in PI subjects that differentiates them from good sleeper controls (GSC); 2) We demonstrated that regional brain glucose metabolism shows prominent diurnal variation in healthy adults, most likely reflecting the influence of the circadian system on brainstem-hypothalamic arousal centers; 3) We showed that , compared to GSC, PI had significantly higher whole brain metabolism during wakefulness and non-rapid eye movement (NREM) sleep, and smaller sleep-related reductions in regional metabolism throughout brainstem, limbic, and frontal systems. The general aim of this application is to test a refined model of insomnia neurobiology by tying together our novel observations with recent neuroscience discoveries in sleep-wake regulation. Our model views insomnia as a disorder of sleep-wake state regulation, reflected across symptom, physiological, and functional anatomic levels. In the proposed study we will focus on the diurnal variation we have observed in insomnia symptoms, and on homeostatic sleep-wake regulation, because of its potential relevance to behavioral treatments for PI that involve sleep restriction. We will test our model using three strategies: 1) Examining diurnal variation and sleep-wake state as naturalistic neurobiological probes, obtaining FDG PET studies during morning (a.m.) wakefulness, evening (p.m.) wakefulness, and NREM sleep. 2) Correlating a.m. wakefulness, p.m. wakefulness, and NREM sleep regional metabolism with concurrent symptom reports and physiological data. 3) Using one night of total sleep deprivation (TSD) as an experimental probe to examine homeostatic sleep-wake regulation. We will study 33 adults with PI and 33 age and sex-matched GSC. We will test three following Specific Aims:
Specific Aim 1. To characterize diurnal patterns of regional brain metabolism in PI and GSC.
Specific Aim 2. To examine relationships between regional brain metabolism and concurrent insomnia symptoms (waking and sleep-related) and physiological data (EEG, HRV) in PI.
Specific Aim 3. To examine homeostatic sleep regulation in PI and GSC by comparing changes in regional brain metabolism during NREM sleep before and after TSD in each group. The proposed study will use novel methods to advance our understanding of the neurobiology of PI, including aspects of neurobiology that are relevant to behavioral treatments. Insomnia is a common and impairing health condition, but we know very little about its causes, particularly in terms of brain function. This study will examine brain function in individuals with and without insomnia during wakefulness and during sleep; will examine how brain function is related to daytime and sleep symptoms; and will study the response of these individuals to one night of sleep deprivation. Results of this study could help us to better understand how the brain functions during sleep and wakefulness in people with insomnia, and how behavioral treatments (such as sleep restriction) might work. ? ? ? ?

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Muehrer, Peter R
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University of Pittsburgh
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