Circadian rhythm sleep disorders occur when individuals attempt to sleep at the wrong circadian time. The misalignment between the internal circadian timing system and the external environment is typically due to either an alteration in the functioning of the circadian timing system (e.g., delayed or advanced sleep phase disorder) or to changes in the external environment (e.g., jet lag). However, the clinical presentation of most of the circadian rhythm sleep disorders is influenced by a combination of physiologic, behavioral, and environmental factors. These disorders lead to complaints of insomnia and excessive daytime sleepiness, with impairment in important areas of functioning and quality of life. Current treatments, such as timed exposure to bright light and exogenous melatonin, primarily serve to align the timing of circadian rhythms or increase the strength of the circadian signal. Although these treatments are effective, their use in clinical practice has been limited by the availability of adequate diagnostic tools and large-scale randomized controlled clinical trials. The rapid advances in our understanding of the molecular, cellular, and physiologic basis of circadian regulation and the pathophysiology of these disorders will lead to more targeted and effective treatments.
"Consequently, misalignment between internal circadian time and wakefulness-sleep schedules leads to impaired wakefulness and sleep disturbance. Circadian misalignment may occur during shift work, jet lag or certain circadian rhythm disorders [4,5]. One of the effects of circadian misalignment is a reduction in total sleep time, but circadian misalignment may also affect sleep architecture. "
[Show abstract][Hide abstract] ABSTRACT: Circadian misalignment affects total sleep time, but it may also affect sleep architecture. The objectives of this study were to examine intra-individual effects of circadian misalignment on sleep architecture and inter-individual relationships between sleep stages, cortisol levels and insulin sensitivity. Thirteen subjects (7 men, 6 women, age: 24.3±2.5 y; BMI: 23.6±1.7 kg/m2) stayed in a time blinded respiration chamber during three light-entrained circadian cycles (3x21h and 3x27h) resulting in a phase advance and a phase delay. Sleep was polysomnographically recorded. Blood and salivary samples were collected to determine glucose, insulin and cortisol concentrations. Intra-individually, a phase advance decreased rapid eye movement (REM) sleep and slow-wave sleep (SWS), increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. A phase delay increased REM sleep, decreased stage 2 sleep, increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. Moreover, circadian misalignment changed REM sleep distribution with a relatively shorter REM sleep during the second part of the night. Inter-individually, REM sleep was inversely associated with cortisol levels and HOMA-IR index. Circadian misalignment, both a phase advance and a phase delay, significantly changed sleep architecture and resulted in a shift in rem sleep. Inter-individually, shorter REM sleep during the second part of the night was associated with dysregulation of the HPA-axis and reduced insulin sensitivity.
Trial Registration: International Clinical Trials Registry Platform NTR2926 http://apps.who.int/trialsearch/
PLoS ONE 08/2013; 8(8):e72877. DOI:10.1371/journal.pone.0072877 · 3.23 Impact Factor
"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). Virtually all physiological systems function on a rhythmic basis, and timing of their cycles is entrained through the influences of ambient light, physical activity, and feeding. "
[Show abstract][Hide abstract] ABSTRACT: Effective noninvasive interventions for insomnia are needed. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM™) is a noninvasive, electroencephalography (EEG)-based method to facilitate greater client-unique, autocalibrated improvements of balance and harmony in cortical neural oscillations. This study explores using HIRREM for insomnia. Twenty subjects, with an Insomnia Severity Index (ISI) score of ≥15 (14 women, mean age 45.4, mean ISI 18.6), were enrolled in this randomized, unblinded, wait-list control, crossover, superiority study. Subjects were randomized to receive 8-12 HIRREM sessions over 3 weeks, plus usual care (HUC), or usual care alone (UC). Pre- and post-HIRREM data collection included ISI (primary outcome), and many secondary, exploratory measures (CES-D, SF-36, HR, BP, neurocognitive testing, and VAS scales). The UC group later crossed over to receive HIRREM. ISI was also repeated 4-6 weeks post-HIRREM. All subjects completed the primary intervention period. Analysis for differential change of ISI in the initial intervention period for HUC versus UC showed a drop of 10.3 points (95% CI: -13.7 to -6.9, P < 0.0001, standardized effect size of 2.68). Key secondary outcomes included statistically identical differential change for the crossed-over UC group, and persistence of the effect on the ISI up to > 4 weeks post-HIRREM. Differential change in the HUC group was also statistically significant for CES-D (-8.8, 95% CI: -17.5 to -0.1, P = 0.047), but other exploratory outcomes were not statistically significant. For all receiving HIRREM (n = 19), decreased high-frequency total power was seen in the bilateral temporal lobes. No adverse events were seen. This pilot clinical trial, the first using HIRREM as an intervention, suggests that HIRREM is feasible and effective for individuals having moderate-to-severe insomnia, with clinically relevant, statistically significant benefits based on differential change in the ISI. Effects persisted for 4 weeks after completion of HIRREM. Larger controlled clinical trials are warranted.
Brain and Behavior 11/2012; 2(6):814-24. DOI:10.1002/brb3.101 · 2.24 Impact Factor
"Genetic sleep disorders may represent another target for PDE-inhibition therapy. For instance, in advanced sleep-phase syndrome, patients report daytime somnolence and difficulties to sleep at night , . This syndrome is associated with a specific mutation in the human clock genes Per2 and CKI delta , , and current treatments include phototherapy and the use of chronobiotics such as melatonin (or its analogs ramelteon and tasimelteon) or armodafinil –. "
[Show abstract][Hide abstract] ABSTRACT: The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.
PLoS ONE 05/2012; 7(5):e37121. DOI:10.1371/journal.pone.0037121 · 3.23 Impact Factor
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