Optimal Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Reduces Daytime Resting Heart Rate in Prediabetes: A Randomized Controlled Study.

Background It has been widely recognized that obstructive sleep apnea (OSA) is linked to cardiovascular disease. Yet, randomized controlled studies failed to demonstrate a clear cardiovascular benefit from OSA treatment, mainly because of poor adherence to continuous positive airway pressure (CPAP). To date, no prior study has assessed the effect of CPAP treatment on daytime resting heart rate, a strong predictor of adverse cardiovascular outcomes and mortality. Methods and Results We conducted a randomized controlled study in 39 participants with OSA and prediabetes, who received either in-laboratory all-night (ie, optimal) CPAP or an oral placebo for 2 weeks. During daytime, participants continued daily activities outside the laboratory. Resting heart rate was continuously assessed over 19 consecutive days and nights using an ambulatory device consisting of a single-lead ECG and triaxis accelerometer. Compared with placebo, CPAP reduced daytime resting heart rate (treatment difference, -4.1 beats/min; 95% CI, -6.5 to -1.7 beats/min; P=0.002). The magnitude of reduction in daytime resting heart rate after treatment significantly correlated with the magnitude of decrease in plasma norepinephrine, a marker of sympathetic activity (r=0.44; P=0.02), and the magnitude of decrease in OSA severity (ie, apnea-hypopnea index [r=0.48; P=0.005], oxygen desaturation index [r=0.50; P=0.003], and microarousal index [r=0.57; P<0.001]). Conclusions This proof-of-concept randomized controlled study demonstrates, for the first time, that CPAP treatment, when optimally used at night, reduces resting heart rate during the day, and therefore has positive cardiovascular carry over effects. These findings suggest that better identification and treatment of OSA may have important clinical implications for cardiovascular disease prevention. Registration URL: https:/// www.clini​caltr​ials.gov; Unique identifier: NCT01156116.

Nicotine increases sleep spindle activity.

Studies have shown that both nicotine and sleep spindles are associated with enhanced memorisation. Further, a few recent studies have shown how cholinergic input through nicotinic and muscarinic receptors can trigger or modulate sleep processes in general, and sleep spindles in particular. To better understand the interaction between nicotine and sleep spindles, we compared in a single blind randomised study the characteristics of sleep spindles in 10 healthy participants recorded for 2 nights, one with a nicotine patch and one with a sham patch. We investigated differences in sleep spindle duration, amplitude, intra-spindle oscillation frequency and density (i.e. spindles per min). We found that under nicotine, spindles are more numerous (average increase: 0.057 spindles per min; 95% confidence interval: [0.025-0.089]; p = .0004), have higher amplitude (average amplification: 0.260 µV; confidence interval: [0.119-0.402]; p = .0032) and last longer (average lengthening: 0.025 s; confidence interval: [0.017-0.032]; p = 2.7e-11). These results suggest that nicotine can increase spindle activity by acting on nicotinic acetylcholine receptors, and offer an attractive hypothesis for common mechanisms that may support memorisation improvements previously reported to be associated with nicotine and sleep spindles.

Sleep restriction increases free fatty acids in healthy men.

AIMS/HYPOTHESIS: Sleep loss is associated with insulin resistance and an increased risk for type 2 diabetes, yet underlying mechanisms are not understood. Elevation of circulating non-esterified (i.e. free) fatty acid (NEFA) concentrations can lead to insulin resistance and plays a central role in the development of metabolic diseases. Circulating NEFA in healthy individuals shows a marked diurnal variation with maximum levels occurring at night, yet the impact of sleep loss on NEFA levels across the 24 h cycle remains unknown. We hypothesised that sleep restriction would alter hormones that are known to stimulate lipolysis and lead to an increase in NEFA levels. METHODS: We studied 19 healthy young men under controlled laboratory conditions with four consecutive nights of 8.5 h in bed (normal sleep) and 4.5 h in bed (sleep restriction) in randomised order. The 24 h blood profiles of NEFA, growth hormone (GH), noradrenaline (norepinephrine), cortisol, glucose and insulin were simultaneously assessed. Insulin sensitivity was estimated by a frequently sampled intravenous glucose tolerance test. RESULTS: Sleep restriction relative to normal sleep resulted in increased NEFA levels during the nocturnal and early-morning hours. The elevation in NEFA was related to prolonged nocturnal GH secretion and higher early-morning noradrenaline levels. Insulin sensitivity was decreased after sleep restriction and the reduction in insulin sensitivity was correlated with the increase in nocturnal NEFA levels. CONCLUSIONS/INTERPRETATION: Sleep restriction in healthy men results in increased nocturnal and early-morning NEFA levels, which may partly contribute to insulin resistance and the elevated diabetes risk associated with sleep loss.

The effects of extended bedtimes on sleep duration and food desire in overweight young adults: a home-based intervention.

INTRODUCTION: Sleep curtailment is an endemic behavior in modern society. Well-controlled laboratory studies have shown that sleep loss in young adults is associated with increased desire for high-calorie food and obesity risk. However, the relevance of these laboratory findings to real life is uncertain. We conducted a 3 week, within-participant, intervention study to assess the effects of extended bedtimes on sleep duration and food desire under real life conditions in individuals who are at risk for obesity. METHODS: Ten overweight young adults reporting average habitual sleep duration of less than 6.5 h were studied in the home environment. Habitual bedtimes for 1-week (baseline) were followed by bedtimes extended to 8.5 h for 2-weeks (intervention). Participants were unaware of the intervention until after the baseline period. Participants received individualized behavioral counseling on sleep hygiene on the first day of the intervention period. Sleep duration was recorded by wrist actigraphy throughout the study. Participants rated their sleepiness, vigor and desire for various foods using visual analog scales at the end of baseline and intervention periods. RESULTS: On average, participants obtained 1.6 h more sleep with extended bedtimes (5.6 vs. 7.1; P < 0.001) and reported being less sleepy (P = 0.004) and more vigorous (P = 0.034). Additional sleep was associated with a 14% decrease in overall appetite (P = 0.030) and a 62% decrease in desire for sweet and salty foods (P = 0.017). Desire for fruits, vegetables and protein-rich nutrients was not affected by added sleep. CONCLUSIONS: Sleep duration can be successfully increased in real life settings and obtaining adequate sleep is associated with less desire for high calorie foods in overweight young adults who habitually curtail their sleep.

Detection of cortical slow waves in the sleep EEG using a modified matching pursuit method with a restricted dictionary.

In this paper, an innovative knowledge-based methodological framework to detect sleep slow waves (SSW) in the human sleep electroencephalogram (EEG) is proposed. Based on a restricted matching pursuit (RMP) algorithm, automatic pattern recognition of SSW is implemented using a small dictionary of Gabor functions modeling the target waveform morphological characteristics. The method describes EEG signals in terms of SSW properties and provides detection thresholds based on the largest MP coefficients. A computer software implementation of this new method was tested on a database of overnight polysomnographic recordings collected in 15 young healthy subjects and visually scored by a trained sleep expert. In addition to full automation and fast application, the results obtained from the RMP algorithm, and evaluated using a rigorous performance evaluation metrics, showed excellent agreement as compared with expert scoring, with 97% of correct detections and a concordance of 67% in SSW time position and duration. The performances demonstrated by this new method were superior to that of a canonical detection algorithm introduced earlier, with an equivalent sensitivity but a significant 12% increase in precision ( p = 0.0002). By mimicking the way human processes information while scoring SSW, the RMP algorithm proves stable over time and sleep/wake states, and may thus be used with virtually no human intervention.

Temporal disorganization of circadian rhythmicity and sleep-wake regulation in mechanically ventilated patients receiving continuous intravenous sedation.

OBJECTIVES: Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation. DESIGN: Observational study. SETTING: Academic medical intensive care unit. PATIENTS: Critically ill patients receiving MV and intravenous sedation. METHODS: Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF95, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously. MEASUREMENTS AND RESULTS: We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF95 was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF95 during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64). CONCLUSIONS: The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome.

CONTEXT: Women with polycystic ovary syndrome (PCOS) are insulin resistant and have a high risk of early-onset diabetes and cardiovascular disease. Obstructive sleep apnea (OSA) has adverse cardiometabolic consequences and is highly prevalent in women with PCOS. We sought to determine whether continuous positive airway pressure (CPAP) treatment of OSA has beneficial effects on cardiometabolic function in PCOS. METHODS: Laboratory polysomnography and cardiometabolic measurements including insulin sensitivity and secretion (iv glucose tolerance test); 24-h profiles of plasma catecholamines, cortisol, and leptin; and daytime profiles of blood pressure and cardiac autonomic activity (heart rate variability) were obtained at baseline and again after 8 wk of home CPAP treatment with daily usage monitoring. RESULTS: CPAP treatment modestly improved insulin sensitivity after controlling for body mass index (P = 0.013). The change in insulin sensitivity correlated positively with CPAP use (adjusted P = 0.027) and negatively with body mass index (adjusted P = 0.003). Daytime and nighttime norepinephrine levels were decreased after CPAP (P = 0.002), and the reductions were greater with increased CPAP use (P = 0.03). Epinephrine, cortisol, and leptin levels were not changed significantly. Daytime diastolic blood pressure decreased by an average of 2.3 mm Hg after CPAP (P = 0.035). Cardiac sympathovagal balance was 44% lower (P = 0.007) after CPAP, reflecting a shift toward lower sympathetic activity. CONCLUSIONS: In young obese women with PCOS, successful treatment of OSA improves insulin sensitivity, decreases sympathetic output, and reduces diastolic blood pressure. The magnitude of these beneficial effects is modulated by the hours of CPAP use and the degree of obesity.

Automated detection of sleep EEG slow waves based on matching pursuit using a restricted dictionary.

In this paper, an original method to detect sleep slow waves (SSW) in electroencephalogram (EEG) recordings is proposed. This method takes advantage of a Matching Pursuit algorithm using a dictionary reduced to Gabor functions reproducing the main targeted waveform characteristics. By describing the EEG signals in terms of SSW properties, the corresponding algorithm is able to identify waveforms based on the largest matching coefficients. The implemented algorithm was tested on a database of whole night sleep EEG recordings collected in 9 young healthy subjects where SSW have been visually scored by an expert. Besides being fully automated and much faster than visual scoring analysis, the results obtained to the proposed method were in excellent agreement with the expert with 98% of correct detections and a 77% concordance in event time position and duration. These results were superior from those of the classical method both in terms of sensibility and precision.

Time of night and first night effects on arousal response in healthy adults.

OBJECTIVE: Several factors, such as homeostatic and circadian influences, may affect the density of cortical and subcortical arousals (AR). The purpose of this study was to examine the time-of-night and the first night effect on AR response. METHODS: AR were classified into microarousals (MA), phases of transitory activation (PAT), delta (D-burst) and K-complex burst (K-burst). The AR density and duration was analyzed during two consecutive nights with the analysis of sleep stage and sleep cycle in thirty-six healthy subjects. RESULTS: D- and K-burst showed a trend toward progressive decline across sleep cycles (p<0.0001). While MA rate was unaffected throughout sleep cycles, PAT index increased across the night (p=0.002). The density and duration of each group of AR exhibited reproducibility without significant differences between nights. An individual inter-night variability in AR density was found independently of night and sleep structure. CONCLUSIONS: While homeostatic and circadian influences affect nighttime subcortical and MA responses, a wakefulness drive modulates the occurrence of AR with movements. Although the pattern of AR responses was highly reliable from the first to second night, the substantial inter-individual variability suggests the existence of an individual susceptibility. SIGNIFICANCE: The first night effect on arousal response is affected by individual susceptibility and circadian and homeostatic influences.

Hypocretin and human African trypanosomiasis.

OBJECTIVES: To detail clinical and polysomnographic characteristics in patients affected with Trypanosoma brucei gambiense (Tb.g.) human African trypanosomiasis (HAT) at different stages of evolution and to measure and compare cerebrospinal fluid (CSF) levels of hypocretin-1 with narcoleptic patients and neurologic controls. METHODS: Twenty-five untreated patients affected with T.b.g. HAT were included. The patients were evaluated using a standardized clinical evaluation and a specific interview on sleep complaints. Diagnosis of stages I and II and intermediate stage was performed by CSF cell count and/or presence of trypanosomes: 4 patients were classified as stage II, 13 stage I, and 8 "intermediate" stage. Seventeen untreated patients completed continuous 24-hour polysomnography. We measured CSF levels of hypocretin-1 in all patients at different stages and evolutions, and we compared the results with 26 patients with narcolepsy-cataplexy and 53 neurologic controls. RESULTS: CSF hypocretin-1 levels were significantly higher in T.b.g. HAT (423.2 +/- 119.7 pg/mL) than in narcoleptic patients (40.16 +/- 60.18 pg/ mL) but lower than in neurologic controls (517.32 +/- 194.5 pg/mL). One stage I patient had undetectable hypocretin levels and 1 stage II patient showed intermediate levels, both patients (out of three patients) reporting excessive daytime sleepiness but without evidence for an association with narcolepsy. No differences were found in CSF hypocretin levels between patients with HAT stages; however, the presence of major sleep-wake cycle disruptions was significantly associated with lower CSF hypocretin-1 level with a same tendency for the number of sleep-onset rapid eye movement periods. CONCLUSION: The present investigation is not in favor of a unique implication of the hypocretin system in T.b.g. HAT. However, we propose that dysfunction of the hypothalamic hypocretin region may participate in sleep disturbances observed in African trypanosomiasis.

Major depressive disorder, sleep EEG and agomelatine: an open-label study.

This open study evaluates the effect of agomelatine, a melatonergic receptor agonist and 5-HT2C antagonist antidepressant, on sleep architecture in patients suffering from major depressive disorder. Fifteen outpatients with a baseline HAMD score > or = 20 were treated with 25 mg/d agomelatine for 42 d. Polysomographic studies were performed at baseline, day 7, day 14, and day 42. Sleep efficiency, time awake after sleep onset and the total amount of slow-wave sleep (SWS) increased at week 6. The increase of SWS was predominant during the first sleep cycle. The amount of SWS decreased throughout the first four sleep cycles from day 7 and delta ratio increased from day 14 onwards. No change in rapid eye movement (REM) latency, amount of REM or REM density was observed and agomelatine was well tolerated. In conclusion agomelatine improved sleep continuity and quality. It normalized the distribution of SWS sleep and delta power throughout the night.

Sleep structure: a new diagnostic tool for stage determination in sleeping sickness.

Human African trypanosomiasis (HAT), due to the transmission of Trypanosoma brucei (T. b.) gambiense and T. b. rhodesiense by tsetse flies, is re-emerging in inter-tropical Africa. It evolves from the hemolymphatic Stage I to the meningo-encephalitic Stage II. The latter is generally treated with melarsoprol, an arseniate provoking often a deadly encephalopathy. A precise determination of the HAT evolution stage is therefore crucial. Stage II patients show: (i) a deregulation of the 24-h distribution of the sleep-wake alternation; (ii) an alteration of the sleep structure, with frequent sleep onset rapid eye movement (REM) periods (SOREMPs). Gambian HAT was diagnosed in eight patients (four, Stage II; three, Stage I; one, "intermediate" case) at the trypanosomiasis clinic at Viana (Angola). Continuous 48-h polysomnography was recorded on Oxford Medilog 9000-II portable systems before and after treatment with melarsoprol (Stage II) or pentamidine (Stage I and "intermediate" stage). Sleep traces were visually analyzed in 20-s epochs using the PRANA software. Stage II patients showed the complete sleep-wake syndrome, partly reversed by melarsoprol 1 month later. Two Stage I patients did not experience any of these alterations. However, the "intermediate" and one Stage I patients exhibited sleep disruptions and/or SOREMPs, persistent after pentamidine treatment. Polysomnography may represent a diagnostic tool to distinguish the two stages of HAT. Especially, SOREMPs appear shortly after the central nervous system invasion by trypanosomes. The reversibility of the sleep-wake cycle and sleep structure alterations after appropriate treatment constitutes the basis of an evaluation of the healing process.

Effects of sleep deprivation on spontaneous arousals in humans.

STUDY OBJECTIVES: The hierarchical definition of arousals from sleep includes a range of physiologic responses including microarousals, delta and K-complex bursts, and variations in autonomic system. Whether patterns in slow-wave electroencephalographic activity and autonomic activation are primary forms of arousal response can be addressed by studying effects of total sleep deprivation. We therefore examined changes in arousal density during recovery sleep in healthy subjects. DESIGN: Participants spent 6 consecutive 24-hour periods in the laboratory. Nights 1 and 2 were baseline nights followed by 64-hour total sleep deprivation, then 2 consecutive recovery nights. SETTING: Sleep-deprivation protocol was conducted under laboratory conditions with continuous behavioral and electrophysiologic monitoring. PARTICIPANTS: Twelve drug-free men aged 27.4 +/- 7.9 years were studied. None reported sleepiness or altered sleep-wake cycle, and none had neurologic, psychiatric or sleep disorders. INTERVENTION: N/A. MEASUREMENTS AND RESULTS: Arousals were classified into 4 levels: microarousals, phases of transitory activation, and delta and K-complex bursts. Sleep deprivation induced changes in the density of considered arousals except phases of transitory activation, with a distinct pattern among the different types. The greatest change was found for microarousals, which showed a significant decrease in the first recovery night (P = .01), with return to baseline thereafter. A fall in K-complex and delta-burst density was noted in the first recovery night, not, however, reaching statistical significance. The phases of transitory activation rate were virtually unaffected throughout the experimental nights. CONCLUSIONS: We conclude that homeostatic sleep processes exert an inhibitory effect on arousal response from sleep with a significant effect only on the microarousal density. Decreased delta and K-complex burst rates, though not significant, support the hypothesis that they may be activating processes, probably modulated by factors independent from those implicated in cortical arousal.

Heart rate activation during spontaneous arousals from sleep: effect of sleep deprivation.

OBJECTIVE: Arousal (AR) from sleep is associated with an autonomic reflex activation raising blood pressure and heart rate (HR). Recent studies indicate that sleep deprivation may affect the autonomic system, contributing to high vascular risk. Since in sleep disorders a sleep fragmentation and a partial sleep deprivation occurs, it could be suggested that the cardiovascular effects observed at AR from sleep might be physiologically affected when associated with sleep deprivation. The aim of the study was to examine the effect of sleep deprivation on cardiac arousal response in healthy subjects. METHODS: Seven healthy male subjects participated in a 64 h sleep deprivation protocol. Arousals were classified into four groups, i.e. >3<6 s, >6<10 s, >10<15 s and >15 s, according to their duration. Pre-AR HR values were measured during 10 beats preceding the AR onset, and the event-related HR fluctuations were calculated during the 20 beats following AR onset. As an index of cardiac activation, the ratio of highest HR in the post-AR period over the lowest recorded before AR (HR ratio) was calculated. RESULTS: For AR lasting less than 10 s, the occurrence of AR induces typical HR oscillations in a bimodal pattern, tachycardia followed by bradycardia. For AR lasting more than 10 s, i.e. awakenings, the pattern was unimodal with a more marked and sustained HR rise. The HR response was consistently similar across nights, during NREM and REM sleep, without difference between conditions. CONCLUSIONS: Overall, total sleep deprivation appeared to have no substantial effect on cardiac response to spontaneous arousals and awakenings from sleep in healthy subjects. Further studies are needed to clarify the role of chronic sleep deprivation on cardiovascular risk in patients with sleep disorders. SIGNIFICANCE: In healthy subjects acute prolonged sleep deprivation does not affect the cardiac response to arousal.

Twenty-four-hour disruption of the sleep-wake cycle and sleep-onset REM-like episodes in a rat model of African trypanosomiasis.

STUDY OBJECTIVES: Patients with human African trypanosomiasis (sleeping sickness) due to the inoculation of Trypanosoma brucei gambiense or rhodesiense show a major disruption of the 24-hour sleep-wake distribution, accompanied by the occurrence of sleep-onset rapid-eye-movement (REM) sleep episodes, proportional to the severity of the illness. Although animal models of human African trypanosomiasis have been developed to understand the pathogenic mechanisms leading to immune alterations, the development of an animal model featuring the alterations of endogenous biologic rhythms remains a necessity. ANIMALS: Sprague-Dawley rats (N = 10) entrained to a 12:12-hour dark-light regimen. INTERVENTIONS: Rats were infected with Trypanosoma brucei brucei AnTat 1.1E and instrumented with electrocorticographic and electromyographic electrodes. Polysomnography was recorded continuously from 2 days before infection until the animal's death. MEASUREMENTS AND RESULTS: The analysis of the spontaneous sleep-wake architecture revealed an increased proportion of slow-wave sleep (SWS) and a decreased amount of wakefulness 2 days before death. Considerable sleep fragmentation was observed in the infected rats, with numerous changes in sleep-wake stages and an increased number of episodes of wakefulness and SWS. Infected rats presented a fragmented pattern of SWS and a marked reduction in the mean paradoxical-sleep (PS) latency, resulting in a considerable disruption of the PS-SWS sequences. Abnormal transitions, particularly the appearance of sleep-onset REM episodes, marked the disruption of the internal sleep structure. The electrocorticogram traces were modified during SWS, with the occurrence of abnormal hypersynchronic slow waves and a disappearance of spindles. CONCLUSION: The Trypanosoma brucei brucei-infected rat is a good model of the syndrome seen in human African trypanosomiasis, ie, the 24-hour disruption of the sleep-wake cycle and the occurrence of sleep-onset REM-like sleep episodes.

Daytime sleepiness during Ramadan intermittent fasting: polysomnographic and quantitative waking EEG study.

During the lunar month of Ramadan, Muslims abstain from eating, drinking and smoking from sunrise to sunset. We reported previously that Ramadan provokes a shortening in nocturnal total sleep time by 40 min, an increase in sleep latency, and a decrease in slow-wave sleep (SWS) and rapid eye movement (REM) sleep duration during Ramadan. During the same study, the effects of Ramadan intermittent fasting on daytime sleepiness were also investigated in eight healthy young male subjects using a quantitative waking electroencephalograph (EEG) analysis following the multiple sleep latency test (MSLT) procedure. This procedure was combined with subjective alertness and mood ratings and was conducted during four successive experimental sessions: (1) baseline (BL) 15 days before Ramadan, (2) beginning of Ramadan (R11) on the 11th day of Ramadan, (3) end of Ramadan (R25) on the 25th day of Ramadan, (4) recovery 2 weeks after Ramadan (AR). During each session, four 20-min nap opportunities (MSLTs) were given at 10:00, 12:00, 14:00 and 16:00 h and were preceded by rectal temperature readings. Nocturnal sleep was recorded before each daytime session. Subjective daytime alertness did not change in R25 but decreased in R11 at 12:00 h, and subjective mood decreased at 16:00 h, both in R11 and R25. During the MSLT, mean sleep latency decreased by an average of 2 min in R11 (especially at 10:00 and 16:00 h) and 6 min in R25 (especially at 10:00 and 12:00 h) compared with BL. There was an increase in the daily mean of waking EEG absolute power in the theta (5.5-8.5 Hz) frequency band. Significant correlations were found between sleep latency during the MSLT and the waking EEG absolute power of the fast alpha (10.5-12.5 Hz), sigma (11.5-15.5 Hz) and beta (12.5-30 Hz) frequency bands. Sleep latency was also related to rectal temperature. In conclusion, Ramadan diurnal fasting induced an increase in subjective and objective daytime sleepiness associated with changes in diurnal rectal temperature.

Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG.

RATIONALE: Modafinil is a wake-promoting agent that affects hypothalamic structures involved in the homeostatic and circadian regulation of vigilance. Administered during sleep deprivation, it reduces the need for prolonged recovery sleep and decreases the rebound in EEG slow-wave activity. These diachronic effects suggest an action of modafinil on a homeostatic sleep regulatory process. OBJECTIVES: The aim of this study was to determine whether modafinil, in comparison to the d-amphetamine reference psychostimulant and to placebo, interferes with the vigilance regulatory processes reflected in the EEG during waking. METHODS: Thirty-three healthy subjects were investigated during 60 h of sustained wakefulness in a double-blind placebo-controlled parallel-design study. A 4-min maintenance-of-wakefulness test administered hourly allowed the concomitant assessment of alertness and waking EEG activity. The effects of equipotent psychostimulant dosages (modafinil 300 mg and d-amphetamine 20 mg) were evaluated at the beginning of the first sleep deprivation night, at the end of the second sleep deprivation night and in the afternoon preceding the first recovery night. RESULTS: One hour following ingestion, both psychostimulants increased alertness during 10-12 h, independently of the time of administration. At the level of the waking EEG, d-amphetamine attenuated the natural circadian rhythm of the different frequency bands and suppressed the sleep deprivation-related increase in low frequency (0.5-7 Hz) powers. In contrast, modafinil, which exhibited a transient amphetamine-like effect, had slight effect on circadian rhythms. Its selective action was characterized by maintenance of the alpha(1) (8.5-11.5 Hz) EEG power, which under placebo exhibited a homeostatic decrease paralleling that of alertness with a circadian trough at night. CONCLUSIONS: These findings demonstrate that the alertness-promoting effects of modafinil and d-amphetamine involve distinct EEG activities and do not reside on the same vigilance regulatory processes. While d-amphetamine inhibits the expression of a sleep-related process, probably through a direct cortical activation masking EEG circadian rhythms, modafinil, through a synchronic effect, preferentially disrupts the homeostatic down-regulation of a waking drive.