1998), 10–25% may have clinical depression, and 20–30% have anxiety disorder (Ohayon and Roth 2003; Taylor et al. 2005). Chronic insomnia is associated with reduced quality of life, higher absenteeism, impaired

job performance, and higher healthcare utilization (Kuppermann et al. 1995; Simon and VonKorff 1997). In a large population-based study, a linear relationship was demonstrated between insomnia prevalence and number of self-reported comorbid medical disorders (Budhiraja et al. 2011). Insomnia severity has been correlated with suicidal thinking in a clinical trial Inhibitors,research,lifescience,medical population (McCall et al. 2010). Although these cross-sectional associations are often interpreted to suggest that a variety of pathologies can result in secondary insomnia, prospective studies have found insomnia to be a risk factor Inhibitors,research,lifescience,medical for acute myocardial infarction (Laugsand et al. 2011) and depression (Jaussent et al. 2011). In long-term follow-up of 1741 individuals who had undergone polysomnography, insomnia was found to confer an independent and significantly increased risk for mortality (Vgontzas et al. 2010). The question of how or why insomnia should be a risk factor for other pathologies likely overlaps with the question of what processes are responsible for the pathogenesis of insomnia itself. To answer one or both of these questions, conceptualizations and data from several lines of inquiry may be helpful. The “hyperarousal” Inhibitors,research,lifescience,medical theory (Perlis et al. 1997) highlights

interplay between psychological Inhibitors,research,lifescience,medical and physiological factors in the etiology and perpetuation of chronic insomnia, including increased SRT1720 mw autonomic activity (Monroe 1967; Adam et al. 1986); activation of neuroendocrine and neuroimmunological axes (Vgontzas et al. 2001; Burgos et al. 2006), and altered brain metabolism, especially during the

night (Nofzinger et al. 2004). For instance, compared with normal controls, insomnia patients show significantly increased ratio of low- to high-frequency spectral power (LF/HF, sympathetic activation) of heart rate variability (Bonnet and Arand 1998), increased production of cortisol (activity of the hypothalamic–pituitary–adrenal Inhibitors,research,lifescience,medical axis) and interleukin-6 (IL-6, activation of neuroimmunological axes) (Riemann et al. 2009), and increased power in higher frequencies as measured by spectral analysis of the sleep electroencephalogram (EEG) at sleep onset (Perlis et al. 2001a) and during nonrapid eye movement (REM) sleep (Perlis et al. 2001b). Greater amplitudes, as measured almost by event-related EEG potentials, were observed in several latency ranges prior to, during, and on awakening (Devoto et al. 2005; Steiger 2007; Yang and Lo 2007; Bastien et al. 2008). Taken together, these data suggest that heightened cortical arousal may be either part of the pathogenesis of chronic primary insomnia or a consequence of it, or both. Disruption of biological rhythms is another way to model the etiology and sequelae of insomnia (Reid and Zee 2009).