Estimating individual optimal sleep duration and potential sleep debt.

In this study, we hypothesized that dynamics of sleep time obtained over consecutive days of extended sleep in a laboratory reflect an individual's optimal sleep duration (OSD) and that the difference between OSD and habitual sleep duration (HSD) at home represents potential sleep debt (PSD). We found that OSD varies among individuals and PSD showed stronger correlation with subjective/objective sleepiness than actual sleep time, interacting with individual's vulnerability of sleep loss. Furthermore, only 1 h of PSD takes four days to recover to their optimal level. Recovery from PSD was also associated with the improvement in glycometabolism, thyrotropic activity and hypothalamic-pituitary-adrenocortical axis. Additionally, the increase (rebound) in total sleep time from HSD at the first extended sleep would be a simple indicator of PSD. These findings confirmed self-evaluating the degree of sleep debt at home as a useful clinical marker. To establish appropriate sleep habits, it is necessary to evaluate OSD, vulnerability to sleep loss, and sleep homeostasis characteristics on an individual basis.

Screening of clock gene polymorphisms demonstrates association of a PER3 polymorphism with morningness-eveningness preference and circadian rhythm sleep disorder.

A system of self-sustained biological clocks controls the 24-h rhythms of behavioral and physiological processes such as the sleep-wake cycle. The circadian clock system is regulated by transcriptional and translational negative feedback loops of multiple clock genes. Polymorphisms in circadian clock genes have been associated with morningness-eveningness (diurnal) preference, familial advanced sleep phase type (ASPT), and delayed sleep phase type (DSPT). We genotyped single-nucleotide polymorphisms in circadian clock genes in 182 DSPT individuals, 67 free-running type (FRT) individuals, and 925 controls. The clock gene polymorphisms were tested for associations with diurnal preference and circadian rhythm sleep disorder (CRSD) phenotypes. The PER3 polymorphism (rs228697) was significantly associated with diurnal preference and the FRT phenotype. The minor allele of rs228697 was more prevalent in evening types than in morning types (sex-adjusted odds ratio (OR), 2.483, Bonferroni-corrected P = 0.012) and in FRT individuals compared with the controls (age- and sex-adjusted OR, 2.021, permutated P = 0.017). Our findings support the notion that PER3 polymorphisms could be a potential genetic marker for an individual's circadian and sleep phenotypes.

Sleepiness induced by sleep-debt enhanced amygdala activity for subliminal signals of fear.

BACKGROUND: Emotional information is frequently processed below the level of consciousness, where subcortical regions of the brain are thought to play an important role. In the absence of conscious visual experience, patients with visual cortex damage discriminate the valence of emotional expression. Even in healthy individuals, a subliminal mechanism can be utilized to compensate for a functional decline in visual cognition of various causes such as strong sleepiness. In this study, sleep deprivation was simulated in healthy individuals to investigate functional alterations in the subliminal processing of emotional information caused by reduced conscious visual cognition and attention due to an increase in subjective sleepiness. Fourteen healthy adult men participated in a within-subject crossover study consisting of a 5-day session of sleep debt (SD, 4-h sleep) and a 5-day session of sleep control (SC, 8-h sleep). On the last day of each session, participants performed an emotional face-viewing task that included backward masking of nonconscious presentations during magnetic resonance scanning. RESULTS: Finally, data from eleven participants who were unaware of nonconscious face presentations were analyzed. In fear contrasts, subjective sleepiness was significantly positively correlated with activity in the amygdala, ventromedial prefrontal cortex, hippocampus, and insular cortex, and was significantly negatively correlated with the secondary and tertiary visual areas and the fusiform face area. In fear-neutral contrasts, subjective sleepiness was significantly positively correlated with activity of the bilateral amygdala. Further, changes in subjective sleepiness (the difference between the SC and SD sessions) were correlated with both changes in amygdala activity and functional connectivity between the amygdala and superior colliculus in response to subliminal fearful faces. CONCLUSION: Sleepiness induced functional decline in the brain areas involved in conscious visual cognition of facial expressions, but also enhanced subliminal emotional processing via superior colliculus as represented by activity in the amygdala. These findings suggest that an evolutionally old and auxiliary subliminal hazard perception system is activated as a compensatory mechanism when conscious visual cognition is impaired. In addition, enhancement of subliminal emotional processing might cause involuntary emotional instability during sleep debt through changes in emotional response to or emotional evaluation of external stimuli.

In vitro circadian period is associated with circadian/sleep preference.

Evaluation of circadian phenotypes is crucial for understanding the pathophysiology of diseases associated with disturbed biological rhythms such as circadian rhythm sleep disorders (CRSDs). We measured clock gene expression in fibroblasts from individual subjects and observed circadian rhythms in the cells (in vitro rhythms). Period length of the in vitro rhythm (in vitro period) was compared with the intrinsic circadian period, τ, measured under a forced desynchrony protocol (in vivo period) and circadian/sleep parameters evaluated by questionnaires, sleep log, and actigraphy. Although no significant correlation was observed between the in vitro and in vivo periods, the in vitro period was correlated with chronotype, habitual sleep time, and preferred sleep time. Our data demonstrate that the in vitro period is significantly correlated with circadian/sleep preference. The findings suggest that fibroblasts from individual patients can be utilized for in vitro screening of therapeutic agents to provide personalized therapeutic regimens for CRSD patients.

Sleep debt elicits negative emotional reaction through diminished amygdala-anterior cingulate functional connectivity.

OBJECTIVES: Sleep debt reportedly increases emotional instability, such as anxiety and confusion, in addition to sleepiness and psychomotor impairment. However, the neural basis of emotional instability due to sleep debt has yet to be elucidated. This study investigated changes in emotional responses that are elicited by the simulation of short-term sleep loss and the brain regions responsible for these changes. SUBJECTS AND METHODS: Fourteen healthy adult men aged 24.1±3.3 years (range, 20-32 years) participated in a within-subject crossover study consisting of 5-day sessions of both sleep debt (4 h for time in bed) and sleep control (8 h for time in bed). On the last day of each session, participants underwent polysomnography and completed the State-Trait Anxiety Inventory and Profile of Mood States questionnaires. In addition, functional magnetic resonance imaging was conducted while performing an emotional face viewing task. RESULTS: Restricted sleep over the 5-day period increased the activity of the left amygdala in response to the facial expression of fear, whereas a happy facial expression did not change the activity. Restricted sleep also resulted in a significant decrease in the functional connectivity between the amygdala and the ventral anterior cingulate cortex (vACC) in proportion to the degree of sleep debt (as indicated by the percentage of slow wave sleep and δ wave power). This decrease was significantly correlated with activation of the left amygdala and deterioration of subjective mood state. CONCLUSION: The results of this study suggest that continuous and accumulating sleep debt that can be experienced in everyday life can downregulate the functional suppression of the amygdala by the vACC and consequently enhance the response of the amygdala to negative emotional stimuli. Such functional alteration in emotional control may, in part, be attributed to the neural basis of emotional instability during sleep debt.

Intrinsic circadian period of sighted patients with circadian rhythm sleep disorder, free-running type.

BACKGROUND: Circadian rhythm sleep disorder, free-running type (FRT), is an intractable sleep disorder in which sleep and wake times progressively delay each day even in normal living environments. This disorder severely affects the social functioning of patients because of periodic nighttime insomnia, excessive daytime sleepiness, and a high rate of comorbid psychiatric disorders. Although abnormal regulation of the biological clock is suspected, the pathophysiology of FRT has yet to be elucidated. In this study, the endogenous circadian period, τ, of FRT patients with normal vision was compared with that of healthy individuals whose circadian rhythms are entrained to a 24-hour cycle. METHODS: Six FRT patients and 17 healthy individuals (9 intermediate chronotypes and 8 evening chronotypes) were subjected to a 7-day, 28-hour sleep-wake schedule according to the forced desynchrony protocol. Phase shifts in melatonin rhythm were measured under constant routine conditions to calculate τ. RESULTS: In FRT patients, τ was significantly longer than in intermediate chronotypes, whereas in evening chronotypes, it ranged widely and was not significantly different from that in FRT patients. Moreover, τ of melatonin rhythm in FRT patients showed no significant correlation with τ of sleep-wake cycles measured before the study. CONCLUSIONS: The findings suggest that although a prolongation of τ may be involved in the onset mechanism of FRT, a prolonged τ is not the only factor involved. It appears that several factors including abnormal entrainment of circadian rhythms are involved in the onset of FRT in a multilayered manner.

Rhythmic expression of circadian clock genes in human leukocytes and beard hair follicle cells.

Evaluating individual circadian rhythm traits is crucial for understanding the human biological clock system. The present study reports characterization of physiological and molecular parameters in 13 healthy male subjects under a constant routine condition, where interfering factors were kept to minimum. We measured hormonal secretion levels and examined temporal expression profiles of circadian clock genes in peripheral leukocytes and beard hair follicle cells. All 13 subjects had prominent daily rhythms in melatonin and cortisol secretion. Significant circadian rhythmicity was found for PER1 in 9 subjects, PER2 in 3 subjects, PER3 in all 13 subjects, and BMAL1 in 8 subjects in leukocytes. Additionally, significant circadian rhythmicity was found for PER1 in 5 of 8 subjects tested, PER2 in 2 subjects, PER3 in 6 subjects, and BMAL1 in 3 subjects in beard hair follicle cells. The phase of PER1 and PER3 rhythms in leukocytes correlated significantly with that of physiological rhythms. Our results demonstrate that leukocytes and beard hair follicle cells possess an endogenous circadian clock and suggest that PER1 and PER3 expression would be appropriate biomarkers and hair follicle cells could be a useful tissue source for the evaluation of biological clock traits in individuals.

Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial.

BACKGROUND: Antihistamines with strong sedative-hypnotic properties are frequently prescribed for insomnia secondary to allergy, but the potential risks of such administration have not been fully elucidated. SUBJECTS AND METHODS: This randomized, double-blind, placebo-controlled crossover study was conducted to evaluate next-day sleepiness and psychomotor performance following the administration of antihistamines. Twenty-two healthy male participants participated in four drug administration sessions with more than a 1-week interval between the sessions. Either zolpidem 10 mg, or diphenhydramine 50 mg, or ketotifen 1 mg, or a placebo was administered before sleep, and polysomnography was conducted to evaluate sleep. In the morning and afternoon of the day after administration, the participants were evaluated for subjective sleepiness, objective sleepiness, and psychomotor performance. RESULTS: The antihistamines with high blood-brain barrier-crossing efficiency were significantly associated with sleepiness and psychomotor performance decline the next day. Ketotifen showed the strongest carryover effect, followed by diphenhydramine. Compared with the placebo, no significant carryover effect was observed with zolpidem. CONCLUSION: The results suggest that the risk-benefit balance should be considered in the ready use of antihistamines that easily cross the blood-brain barrier for alleviating secondary insomnia associated with allergies.

Sleep apnea and ventricular arrhythmias: Clinical outcome, electrophysiologic characteristics, and follow-up after catheter ablation.

BACKGROUND AND OBJECTIVES: Sleep apnea is highly prevalent in patients with heart disease. However, the association between sleep apnea and ventricular arrhythmias is unclear. The aim of this study was to examine the relationship between sleep apnea and electrophysiologic characteristics and clinical outcome after catheter ablation in patients having ventricular arrhythmias. METHODS AND RESULTS: Forty-four patients with ventricular tachycardia (VT) or premature ventricular complexes (PVCs) without structural heart diseases (57% men; mean age: 55 + or - 15 years) underwent a sleep study. Subjects with an apnea-hypopnea index (AHI) > or = 10/h were considered to have sleep apnea. Electrophysiologic studies were performed on all patients, and 35 patients underwent catheter ablation therapy. Seventeen patients (39%) had sleep apnea with an average AHI of 27 + or - 17/h. Electrophysiologic characteristics of ventricular arrhythmias showed that sites of VT/PVCs origin in the pulmonary artery and the aortic sinus of Valsalva were detected in 27% and 20% patients with sleep apnea, which was a relatively higher rate than that in patients without sleep apnea (8% and 0%, respectively). Successful catheter ablation was achieved in 11 patients (85%) with sleep apnea and 17 (77%) without sleep apnea. During a mean follow-up period of 13.5 + or - 7.3 months after catheter ablation, 5 patients (45%) with sleep apnea and 1 patient (6%) without sleep apnea experienced recurrent VT/PVCs. Comparing the outcome between the two groups, the VT/PVCs recurrence rate was significantly higher in patients with sleep apnea than in those without sleep apnea (p=0.02). CONCLUSIONS: Ventricular arrhythmia patients with sleep apnea have a high recurrence of arrhythmias after successful catheter ablation. Patients with ventricular arrhythmias should be systematically assessed for sleep apnea owing to the potential detrimental effects of sleep apnea in the follow-up period.

Metabolic rate and fuel utilization during sleep assessed by whole-body indirect calorimetry.

The purpose of this study was to examine metabolic rate and substrate oxidation during sleep in relation to time of sleep and sleep stage. Twelve male subjects free from sleep-disordered breathing slept for 469 +/- 8.7 (mean +/- SE) minutes until natural awakening in a whole-body indirect calorimeter, and polysomnographic documentation of sleep was recorded. Energy expenditure decreased during the first half of the night, reached a nadir (a 35% decrease), and remained relatively stable until awakening. Similarly, fat oxidation decreased from the onset of sleep. On the other hand, carbohydrate oxidation showed no remarkable changes from the onset of sleep but began to increase before awakening. Because distribution of sleep stages is not uniform throughout the night, with rapid-eye-movement (REM) sleep tending to appear later in the sleep, effect of sleep stage on energy metabolism was isolated by analysis of covariance with time as a covariate. Subsequent comparison of metabolic rate by 1-way analysis of variance with Bonferroni post hoc analysis revealed that energy expenditure during REM sleep was significantly greater than that during sleep stages 2 and 3/4 (stage 2, 25.248 +/- 0.961; stage 3/4, 24.825 +/- 0.935; REM, 25.712 +/- 0.928 kcal kg(-1) fat-free mass d(-1)). Carbohydrate oxidation during REM sleep was significantly greater than that during sleep stage 3/4 (stage 3/4, 12.229 +/- 1.071; REM, 13.986 +/- 1.291 kcal kg(-1) fat-free mass d(-1)). Respiration quotient was statistically different among sleep stages, but Bonferroni post hoc analysis failed to identify significant differences (stage 2, 0.850 +/- 0.010; stage 3/4, 0.846 +/- 0.011; REM, 0.861 +/- 0.013). The increases in energy expenditure and carbohydrate oxidation during REM sleep are consistent with a notion that changes in energy metabolism in brain are manifested as small fluctuations in whole-body energy metabolism during sleep.

Algorithm for transient response of whole body indirect calorimeter: deconvolution with a regularization parameter.

A whole body indirect calorimeter provides accurate measurement of energy expenditure over long periods of time, but it has limitations to assess its dynamic changes. The present study aimed to improve algorithms to compute O(2) consumption and CO(2) production by adopting a stochastic deconvolution method, which controls the relative weight of fidelity to the data and smoothness of the estimates. The performance of the new algorithm was compared with that of other algorithms (moving average, trends identification, Kalman filter, and Kalman smoothing) against validation tests in which energy metabolism was evaluated every 1 min. First, an in silico simulation study, rectangular or sinusoidal inputs of gradually decreasing periods (64, 32, 16, and 8 min) were applied, and samples collected from the output were corrupted with superimposed noise. Second, CO(2) was infused into a chamber in gradually decreasing intervals and the CO(2) production rate was estimated by algorithms. In terms of recovery, mean square error, and correlation to the known input signal in the validation tests, deconvolution performed better than the other algorithms. Finally, as a case study, the time course of energy metabolism during sleep, the stages of which were assessed by a standard polysomnogram, was measured in a whole body indirect calorimeter. Analysis of covariance revealed an association of energy expenditure with sleep stage, and energy expenditure computed by deconvolution and Kalman smoothing was more closely associated with sleep stages than that based on trends identification and the Kalman filter. The new algorithm significantly improved the transient response of the whole body indirect calorimeter.

Association of sleep-disordered breathing and ventricular arrhythmias in patients without heart failure.

The prevalence and characteristics of sleep-disordered breathing (SDB) in patients with ventricular arrhythmias, such as premature ventricular complexes and ventricular tachycardia, are unknown. Therefore, this study was conducted to evaluate the prevalence of SDB in patients with severe ventricular arrhythmias and normal left ventricular (LV) function. Thirty-five patients (63% men, mean age 57.4 +/- 13.8 years) underwent a sleep study. All patients had ventricular tachycardia or frequent premature ventricular complexes (>or=300/hour) and had been referred to the cardiology department for medication, catheter ablation therapy, or the implantation of a cardioverter-defibrillator. Patients with heart failure with LV ejection fractions <50% were excluded; in the remaining patients, the mean LV ejection fraction was 63.9 +/- 8.0%. Twenty-one patients (60%) had SDB with apnea-hypopnea indexes >or=5/hour, and the average apnea-hypopnea index was 22.7 +/- 17.9/hour. Twelve patients (34%) had moderate to severe SDB, with an average apnea-hypopnea index of 33.6 +/- 16.6/hour. Central dominant sleep apnea was evident in 3 patients with SDB. The average age and body mass index were significantly higher in patients with SDB than in those without SDB (age 62.0 +/- 12.8 vs 50.6 +/- 12.7 years, body mass index 26.3 +/- 4.0 vs 21.2 +/- 2.0 kg/m2). In conclusion, this study found a high prevalence of SDB in patients with ventricular arrhythmias and normal LV function.