Physiologic indexes in chronic insomnia during a constant routine: evidence for general hyperarousal?

STUDY OBJECTIVES: It has been hypothesized that general hyperarousal, present during both sleep and wakefulness, may underlie chronic insomnia. The present study explored, under strictly controlled conditions, whether chronic insomnia is associated with altered physiologic markers of arousal, both in absolute levels and in terms of circadian rhythmicity, relative to controls. DESIGN: A 24-hour constant-routine protocol was implemented to assess physiologic measures. SETTING: The study was conducted in an isolated, temperature- and light-controlled, sound-attenuated sleep laboratory. PARTICIPANTS: Eleven subjects with clinically diagnosed chronic insomnia were compared with 13 healthy matched controls. Interventions: The subjects underwent physiologic parameter recordings and cognitive performance testing during 24 hours of total sleep deprivation under strictly controlled circumstances. MEASUREMENTS AND RESULTS: Cardiovascular parameters, free cortisol, and body temperature were subjected to mixed-model analysis of variance and mixed-model harmonic regression. Overall, no differences were found in either the absolute level or the circadian parameters (amplitude, phase) of these variables between the insomniacs and the control subjects. Conclusions: Although physiologic indexes of arousal were slightly elevated in the insomnia group relative to the controls, the differences between the groups were not statistically significant. This could have been due to a lack of statistical power or could reflect the actual absence of arousal in our sample of chronic insomniacs. Systematic interindividual level differences overwhelmed any differences between the 2 groups, making it unlikely that general hyperarousal was a critical underlying factor in our sample. Earlier findings of hyperarousal in insomnia during studies that allowed sleep may have been specifically related to the sleep state.     

Sleep loss in elderly volunteers

Sleep, performance, and sleepiness were assessed in 10 elderly volunteers (8 women, 2 men; aged 61-77 years) before, during, and after 38 h of sleep loss. Recovery night 1 sleep showed increased total sleep and stages 3 and 4 sleep and decreased stage 1 sleep, wakefulness, brief arousals, and latency to stages 3 and 4 sleep. An increase in stage 4 sleep persisted to the second recovery night. Increased arousal threshold was suggested by a lengthening of respiratory events and a reduction in arousals associated with leg movements. Performance was impaired during sleep loss, associated with an increased tendency to fall asleep. Reported sleepiness increased, except in three subjects who denied sleepiness. Latency to sleep onset declined. All measures returned to basal values after a night of sleep. Sleep in one volunteer failed to respond to sleep loss. With this exception, the response was similar to that reported in younger volunteers, although shorter-lived.     

Prospective comparison of subjective arousal during the pre-sleep period in primary sleep-onset insomnia and normal sleepers

Psychophysiological insomnia (PI) is the most common insomnia subtype, representing 12-15% of all sleep centre referrals. Diagnostic guidelines describe PI as an intrinsic sleep disorder involving both hyperarousal and learned sleep-preventing associations. Whilst evidence for the first component is reasonably compelling, evidence for learned (conditioned) sleep effects is markedly lacking. Indeed, to date no study has attempted to capture directly the conditioned arousal effect assumed to characterize the disorder. Accordingly, the present study explored variations in subjective arousal over time in 15 PI participants (sleep onset type) and 15 normal sleepers (NS). Self-report measures of cognitive arousal, somatic arousal and sleepiness were taken at three time points: 3 h before bedtime (early to mid-evening); 1 h before bedtime (late evening); and in the bedroom at lights out (bedtime) across four, 24-h cycles. Fluctuations in mean arousal and sleepiness values, and in day-to-day variation were examined using analyses of variance. Participants with PI were significantly more cognitive aroused and significantly less sleepy relative to NS, within the bedroom environment. These results support the tenet of conditioned mental arousal to the bedroom, although competing explanations cannot be ruled out. Results are discussed with reference to extant insomnia models.     

Increased EEG sigma and beta power during NREM sleep in primary insomnia

The hyperarousal model of primary insomnia suggests that a deficit of attenuating arousal during sleep might cause the experience of non-restorative sleep. In the current study, we examined EEG spectral power values for standard frequency bands as indices of cortical arousal and sleep protecting mechanisms during sleep in 25 patients with primary insomnia and 29 good sleeper controls. Patients with primary insomnia demonstrated significantly elevated spectral power values in the EEG beta and sigma frequency band during NREM stage 2 sleep. No differences were observed in other frequency bands or during REM sleep. Based on prior studies suggesting that EEG beta activity represents a marker of cortical arousal and EEG sleep spindle (sigma) activity is an index of sleep protective mechanisms, our findings may provide further evidence for the concept that a simultaneous activation of wake-promoting and sleep-protecting neural activity patterns contributes to the experience of non-restorative sleep in primary insomnia.     

Impaired memory consolidation during sleep in patients with functional memory disorder

Functional memory disorder (FMD) is characterized by mnestic and attentional deficits without symptoms of mild cognitive impairment or dementia. FMD usually develops in subjects with high psychosocial stress level and is classified to the somatoform disorders. We assessed memory performance (procedural mirror tracing task, declarative visual and verbal memory task) and other cognitive functions before and after one night of sleep in 12 FMD patients (mean age: 51.7 yrs, 7 females) and 12 healthy subjects matched for age, gender and IQ. Memory performance and other neurocognitive tasks did not differ between the groups at baseline. After one night of sleep, FMD patients showed an impairment of declarative memory consolidation compared to healthy subjects (visual task: p = 0.004; verbal task: p = 0.039). Spectral analysis of sleep-EEG indicated an increased cortical excitation in FMD. We hypothesize that a hyperarousal state in FMD might contribute to sleep disturbance implicating negative effects on declarative memory consolidation.     

Increased EEG sigma and beta power during NREM sleep in primary insomnia

The hyperarousal model of primary insomnia suggests that a deficit of attenuating arousal during sleep might cause the experience of non-restorative sleep. In the current study, we examined EEG spectral power values for standard frequency bands as indices of cortical arousal and sleep protecting mechanisms during sleep in 25 patients with primary insomnia and 29 good sleeper controls. Patients with primary insomnia demonstrated significantly elevated spectral power values in the EEG beta and sigma frequency band during NREM stage 2 sleep. No differences were observed in other frequency bands or during REM sleep. Based on prior studies suggesting that EEG beta activity represents a marker of cortical arousal and EEG sleep spindle (sigma) activity is an index of sleep protective mechanisms, our findings may provide further evidence for the concept that a simultaneous activation of wake-promoting and sleep-protecting neural activity patterns contributes to the experience of non-restorative sleep in primary insomnia.     

Hyperarousal captured in increased number of arousal events during pre‐REM periods in individuals with frequent nightmares

The aim of this study was to investigate hyperarousal in individuals with frequent nightmares (NM participants) by calculating arousal events during nocturnal sleep. We hypothesized an increased number of arousals in NM participants compared with controls, especially during those periods where the probability of spontaneous arousal occurrence is already high, such as non‐rapid eye movement to rapid eye movement transitions (pre‐rapid eye movement periods). Twenty‐two NM participants and 23 control participants spent two consecutive nights in our sleep laboratory, monitored by polysomnography. Arousal number and arousal length were calculated only for the second night, for 10 min before rapid eye movement (pre‐rapid eye movement) and 10 min after rapid eye movement (post‐rapid eye movement) periods, as well as non‐rapid eye movement and rapid eye movement phases separately. Repeated‐measures ANOVA model testing revealed significant Group (NM participants, controls) × Phase (pre‐rapid eye movement, post‐rapid eye movement) interaction in case of the number of arousals. Furthermore, post hoc analysis showed a significantly increased number of arousals during pre‐rapid eye movement periods in NM participants, compared with controls, a difference that disappeared in post‐rapid eye movement periods. We propose that focusing the analyses of arousals specifically on state transitory periods offers a unique perspective into the fragile balance between the sleep‐promoting and arousal systems. This outlook revealed an increased number of arousals in NM participants, reflecting hyperarousal during pre‐rapid eye movement periods.     

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.     

Effect of cognitive arousal on sleep latency, somatic and cortical arousal following partial sleep deprivation

Emerging research has shown that sleepiness, defined as the tendency to fall asleep, is not only determined by sleep pressure and time of day, but also by physiological and cognitive arousal. In this study we evaluated (i) the impact of experimentally induced cognitive arousal on electroencephalogram (EEG) defined sleep latency, and subjective, somatic and cortical arousal, and (ii) whether experimentally induced cognitive arousal enhances performance on a driving simulator test. Twelve healthy sleepers each spent three nights and the following day in the sleep laboratory: an adaptation, a cognitive arousal and a neutral testing day. In the cognitive arousal condition, a visit of a television camera crew took place and subjects were asked to be interviewed. On each testing day, a 5-min heart rate recording, subjective sleepiness and arousal scales, Multiple Sleep Latency Test and a 25-min driving simulator task were scheduled three times at 2-h intervals. Experimentally induced cognitive arousal resulted in significant increases in objective sleep latency. Significantly elevated levels of subjective and somatic arousal--as indexed by a subjective arousal scale and heart rate--were also evidenced following cognitive arousal induction. A marginally significant trend for increased cortical arousal, measured by EEG beta activity, was also found. No effects were found on driving simulator performance. These findings support the concept of cognitive arousal as a significant component in determining sleep latency. In addition, it was illustrated that cognitively induced arousal can provoke increases in somatic and possibly even cortical arousal in normal sleepers. However, this was not accompanied by an enhanced ability to perform adequately on a driving simulator test.     

Vulnerability to stress-related sleep disturbance and hyperarousal

STUDY OBJECTIVES: To determine the presence of a hypothesized trait vulnerability to sleep disturbance and hyperarousal. DESIGN: Polysomnographic assessment of sleep in response to stress during a first night in the laboratory and subsequent physiologic arousal. PARTICIPANTS: One hundred and four individuals (46% men, mean age 40.4 +/- 12.9 years) drawn from a population-based sample. INTERVENTIONS: Individuals were exposed to a first night in the laboratory. MEASUREMENTS AND RESULTS: Participants completed a Likert-scale questionnaire, consisting of 27 items, that assesses sleep disturbance in response to commonly experienced stressful situations. Factor analytic techniques identified a single 9-item factor that was representative of the construct of "stress-related" vulnerability to sleep disturbance. Reliability of the resulting 9-item scale was high (Cronbach's alpha = .83). Individuals with higher scores on this scale, the Ford Insomnia Response to Stress Test (FIRST; median split), had a lower sleep efficiency (P = .001), as well as an increased latency to stage 1 sleep (P = .001) and persistent sleep (P = .002) on the first night of nocturnal polysomnography. Moreover, these high-scoring individuals showed increased arousal as evidenced by an elevated sleep latency on the Multiple Sleep Latency Test compared to individuals with low FIRST scores. Importantly, after controlling for current and past insomnia, the differences between individuals scoring high and low on the FIRST in terms of nocturnal sleep and daytime arousal remained significant. Other stages of sleep (stage 2, slow-wave, and rapid eye movement sleep) were not different between the groups. CONCLUSIONS: These results showing a relationship between FIRST scores and nocturnal polysomnography and Multiple Sleep Latency Test scores have 3 potential implications: (1) the data demonstrate a characteristic that relates to vulnerability to stress-related sleep disturbance as manifested by a first night in the laboratory; (2) the elevated latencies on the Multiple Sleep Latency Test in these individuals, despite significantly disturbed sleep, support the notion of physiologic hyperarousal in these individuals and suggests they may be predisposed to developing chronic primary insomnia; and (3) the vulnerability identified may underlie vulnerability to transient sleep disturbance associated with other sleep-disruptive factors.     

Rapid eye movement sleep parasympathetic activity predicts wake hyperarousal symptoms following a traumatic event

Heart rate variability (HRV) can be used to assess changes in output of the parasympathetic nervous system (PNS). Considering that patients with post-traumatic stress disorder (PTSD) often experience disturbances in sleep, arousal, and autonomic functioning, we sought to explore the association of PNS activity during sleep with hyperarousal symptoms of PTSD. Because a broad literature supports the importance of rapid eye movement (REM) sleep in PTSD, REM-sleep features were specifically examined as predictors of PTSD symptom severity. A total of 90 participants, primarily civilian and female, aged 18–40 years who had experienced a traumatic event in the last 2 years, underwent an ambulatory polysomnography (PSG) acclimation night followed by a second PSG night from which sleep physiological measures were computed. Participants underwent an ambulatory polysomnography (PSG) acclimation night followed by a second PSG night from which sleep physiological measures were computed. PTSD severity was measured using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5). Dependent variables were total PCL-5 score as well as its hyperarousal symptom subscore. Predictors included REM latency, percentage, density, segment length, and an index of parasympathetic tone (root mean square of the successive differences in the R–R interval or RMSSD). Hierarchical regression models were conducted to analyse the association of REM features with PCL-5 total and hyperarousal subscales. Using hierarchical regression, REM-sleep RMSSD accounted for a significant proportion of the variation in outcome variables, even when accounting for other REM-sleep features. The present findings support hypothesised relationships between PTSD symptomatology and REM-sleep physiology and, specifically, that lowered parasympathetic tone in REM may be an important associate of the hyperarousal symptom cluster in PTSD.     

The effect on sleep of being on‐call: an experimental field study

The aim of this study was to: (i) gain more insight into the relationship between being on‐call and sleep and (ii) investigate the role of stress in this relationship. Data were collected by means of an experimental field study with a within‐subject design (two conditions, random order). Ninety‐six students participated during two consecutive nights: a reference night and a simulated on‐call night without an actual call. Participants were told they could be called at any time during the on‐call night. In the case of a call, participants had to perform online tasks for approximately 30 min. Self‐reported sleep quality and the extent to which participants experienced stress during the on‐call period were assessed by means of short questionnaires. Actigraphy was used to obtain objective sleep measures. Results for actigraphy data revealed no significant within‐person differences between conditions. However, participants reported longer sleep onset latencies, more awakenings and more wake after sleep onset during the on‐call night than during the reference night. They also reported more sleep problems and a lower overall sleep quality, and felt less recuperated after the on‐call night. Perceived stress moderated the relationship between being on‐call, on one hand, and the number of awakenings, wake after sleep onset, sleep problems and overall sleep quality, on the other hand. Results show that, even in the absence of an actual call, sleep during on‐call nights is of lower quality and has less restorative value – especially when being on‐call is experienced as stressful.     

Twenty-four-hour structure of sleepiness in morning and evening persons investigated by ultrashort sleep-wake cycle

"Morning" and "evening" persons, defined according to a modified version of the Horne and Ostberg questionnaire, performed the 7/13 min sleep-waking schedule under attempting sleep condition after sleeping for one night in the laboratory, and under the resisting sleep condition after one night of sleep deprivation. Morning types slept significantly more under the attempting sleep condition and showed an earlier rise in nocturnal sleepiness. After sleep deprivation, morning types had a more distinct sleep propensity pattern with well-defined midafternoon and nocturnal sleep gates. In this condition there was a significant interaction between type and time of day with respect to amount of sleep: morning types slept more during the night, and evening types slept more during the day. Based on their amounts of sleep, subjects were also divided into "sleepy" and "alert" types, which were independent from the chronotypology.     

Effects of Experimentally-Induced Sleep Fragmentation on Sleep and Sleepiness

The effects of two levels of sleep fragmentation on sleep and daytime sleepiness were investigated in young adult males. Experimental subjects were informed while awake that tones would be presented periodically throughout the night and that their task was to terminate the tone by taking a deep breath. Eight subjects received tones after each minute of sleep and 8 received tones after each 4 min of sleep. Control subjects (N=8) HI did not receive (ones. The subjects were tested for daytime sleepiness using the Multiple Steep latency Test. It was found that: 1) subjects responded reliably lo tones presented during sleep; 2) behavioral control was accompanied by brief electro-physiological indices of arousal on almost all trials, and occasionally led to fall awakenings; 3) sleep was markedly altered in the 1-min condition; 4) a relatively small effect on sleep (reduced stage 4 sleep) was produced by the 4-min condition, and 5) daytime sleepiness was increased by the 1-min condition but not the 4-min condition. It was concluded that the most parsimonious explanation of these results is (he Continuity of Sleep hypothesis.     

Auditory arousal thresholds of good sleepers and poor sleepers with and without flurazepam.

Auditory arousal thresholds of good (N = 12) and poor (N = 12) sleepers (sleep onset insomniacs) were obtained during stage 2, stage 4, and REM sleep at various times of the night. Despite claims of being "light" sleepers who are easily awakened by noise, poor sleeper auditory arousal thresholds were the same as those of good sleepers. Flurazepam (30 mg) increased the auditory arousal thresholds of poor sleepers (N = 6), but the increase was statistically significant only during the period of peak effect which occurred 1--2 hr after ingestion. Consistent with poor sleeper complaints of trouble falling asleep, the return to sleep (i.e., sleep latency) was significantly longer for poor than for good sleepers following stimulus arousals during the first stage 2 and first stage 4 periods of the night. Sleep latencies for good and poor sleepers did not differ significantly following subsequent arousals. The sleep latency following the first stage 2 stimulus arousal was significantly reduced in poor sleepers during flurazepam-induced sleep.     

Fragmenting sleep diminishes its recuperative value

The recuperative effects of naps fragmented by different rates of electroencephalographic (EEG) arousal were evaluated. Forty healthy subjects with normal hearing and daytime sleep tendency (measured by the Multiple Sleep Latency Test at 10:00 a.m., 12:00 p.m., 2:00 p.m., and 4:00 p.m.) were randomly assigned to one of five conditions. Each was deprived of sleep for one night and then at 8:30 a.m. was given 100 min of natural sleep, sleep with arousals 1/5 min, 1/3 min, 1/1 min, or no sleep. After the recovery nap at 12:00 p.m., 2:00 p.m., 4:00 p.m., and 6:00 p.m., sleep latencies were again evaluated. Mean sleep latencies increased linearly as the rate of arousal during the recuperative nap decreased. Latency in the high-arousal condition was similar to no sleep and lower than natural sleep. The sleep latency of the low-arousal condition was similar to natural sleep and higher than no sleep, whereas latency in the medium arousal condition was intermediate to and differed from both natural sleep and no sleep. Although the natural sleep provided recuperation relative to no sleep or fragmented sleep, it did not restore daytime sleepiness to the screening level.     

The mesograde amnesia of sleep may be attenuated in subjects with primary insomnia

In this study, we pilot tested one of the more controversial components of the Neurocognitive Model of Insomnia; the proposition that subjects with chronic primary insomnia are better able to recall and/or recognize information from sleep onset intervals than good sleeper controls. Nine subjects participated in this pilot study, five of whom had a complaint of insomnia. The remaining four subjects were self-reported good sleeper controls. Subjects were matched for age, sex, and body mass. All subjects spent two nights in the sleep laboratory. The first night served as an adaptation night. The second night served as the experimental night during which a forced awakening and memory task was deployed. In this procedure, subjects were played single-word stimuli across four time periods: at natural sleep onset (Trial 1) and at the sleep onset transitions following three forced awakenings (Trials 2-4 from Stage 2 sleep). All subjects were awakened after about 6 h had elapsed from lights out and were tested for free recall and recognition memory for the word stimuli. The insomnia subjects, tended to identify more of the word stimuli on the recognition task (average for the four trials) and recognized significantly more of the words that were presented at sleep onset proper (Trial 1). This finding suggests that the natural mesograde amnesia of sleep may be attenuated in subjects with insomnia.     

The impact of five nights of sleep restriction on emotional reactivity

An inadequate amount of sleep can negatively affect emotional processing, causing behavioural and neurofunctional changes. However, unlike the condition of total sleep deprivation, which has been extensively studied, the effects of prolonged sleep restriction have received less attention. In this study, we evaluated, for the first time, the effects of five nights of sleep restriction (5 hr a night) on emotional reactivity in healthy subjects. Forty‐two subjects were selected to participate, over two consecutive weeks, in two experimental conditions in counterbalanced order. The subjects were tested the morning after five nights of regular sleep and after five consecutive nights of sleep restriction. During the test, participants evaluated valence and arousal of 90 images selected from the International Affective Picture System. The subjects perceived pleasant and neutral pictures in a more negative way in the sleep‐restriction condition compared to the sleep condition. This effect survived after removing the contribution of mood changes. In contrast, there was no significant difference between conditions for ratings of unpleasant pictures. These results provide the first evidence that an inadequate amount of sleep for five consecutive nights determines an alteration of the evaluation of pleasant and neutral stimuli, imposing a negative emotional bias. Considering the pervasiveness of insufficient sleep in modern society, our results have potential implications for daily life, as well as in clinical settings.     

Relationship of temporal lobe seizures to sleep and arousal: a combined scalp-intracranial electrode study

STUDY OBJECTIVES: The role of arousal from sleep in promoting epileptic seizures is controversial. To examine the question of whether seizures precede or follow arousals from sleep, we defined the timing of temporal lobe seizures in relation to sleep and arousal using combined scalp-intracranial electrodes. DESIGN: Retrospective review of 67 sleep-related mesial temporal lobe seizures in 14 subjects. SETTING: Inpatient epilepsy monitoring laboratory. PATIENTS: Subjects with medically refractory mesial temporal lobe seizures undergoing epilepsy surgery evaluations. INTERVENTIONS: None MEASUREMENTS AND RESULTS: Electroencephalographic (EEG) and/or polygraphic recordings and videotapes were independently reviewed to determine intracranial electrode seizure onset times and time of initial arousal from sleep. In 60 seizures in 13 subjects, intracranial ictal onsets always preceded clinical arousals from sleep. Electrographic signs of arousal in the scalp EEG, defined by the presence of sustained alpha or theta activity, either coincided with or followed, but never preceded, intracranial ictal onsets. In seven seizures in one subject with known seizures upon awakening, intracranial ictal onsets always followed clinical arousals and electrographic signs of arousal from sleep. Seven of the 14 subjects had electrooculogram and chin electromyogram monitoring; in these subjects, no seizures occurred during REM sleep with the majority occurring during NREM stage 2 sleep. CONCLUSIONS: Most sleep-related temporal lobe seizures occurred during NREM sleep and preceded arousals, supporting the premise that processes involved in the initiation and maintenance of NREM sleep play a greater role in facilitating temporal seizures than those involved in promoting REM sleep and arousal. However, arousal from sleep may provoke seizures in exceptional cases.     

Effect of flurazepam, pentobarbital, and caffeine on arousal threshold

After laboratory and procedure adaptation, 6 normal subjects were randomly administered 30 mg flurazepam (twice), 100 mg pentobarbital (twice), 400 mg caffeine (once), and placebo (twice) on nonconsecutive nights. On each night subjects were aroused from standard segments of stage 2 sleep five to eight times with an ascending series of 1,000 Hz tones produced by an audiometer. Arousal threshold and awake threshold after each arousal were measured. Both thresholds were increased by flurazepam and pentobarbital and decreased by caffeine. All of the drugs appeared to modify arousal threshold in a time course fashion such that extreme effects were found during the first half of the night. However, the modifications of waking threshold by caffeine and flurazepam continued throughout the sleep period. The method may be a means of measuring the behavioral time course of drug activity during the sleep period.