Sleep electroencephalogram delta-frequency amplitude, night plasma levels of tumor necrosis factor alpha, and human immunodeficiency virus infection.

We tested the hypothesis that increases in tumor necrosis factor alpha (TNF-alpha) induced by human immunodeficiency virus (HIV) are associated with the increases in slow-wave sleep seen in early HIV infection and the decrease with sleep fragmentation seen in advanced HIV infection. Nocturnal sleep disturbances and associated fatigue contribute to the disability of HIV infection. TNF-alpha causes fatigue in clinical use and promotes slow-wave sleep in animal models. With slow progress toward a vaccine and weak effects from current therapies, efforts are directed toward extending productive life of HIV-infected individuals and shortening the duration of disability in terminal illness. We describe previously unrecognized nocturnal cyclic variations in plasma levels of TNF-alpha in all subjects. In 6 of 10 subjects (1 control subject, 3 HIV-seropositive patients with CD4+ cell number > 400 cells per microliters, and 2 HIV-positive patients with CD4+ cell number < 400 cells per microliters), these fluctuations in TNF-alpha were coupled to the known rhythm of electroencephalogram delta amplitude (square root of power) during sleep. This coupling was not present in 3 HIV-positive subjects with CD4+ cell number < 400 cells per microliters and 1 control subject. In 5 HIV subjects with abnormally low CD4+ cell counts ( < 400 cells per microliters), the number of days since seroconversion correlated significantly with low correlation between TNF-alpha and delta amplitude. We conclude that a previously unrecognized normal, physiological coupling exists between TNF-alpha and delta amplitude during sleep and that the lessened likelihood of this coupling in progressive HIV infection may be important in understanding fatigue-related symptoms and disabilities.

Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature.

Modafinil is an alerting substance that is considered safer than amphetamine with fewer side effects. Although modafinil has been used successfully to treat narcolepsy, relatively little is known about its ability to ameliorate fatigue and declines in mental performance due to sleep deprivation (SD) in a normal population. Forty-one military subjects received either 300 mg of modafinil, 20 mg of d-amphetamine, or placebo on 3 separate occasions during 64 hours of continuous cognitive work and sleep loss. Three drug treatments were given: at 23.30 hours and 05.30 hours during the first and second SD nights, respectively, and once at 15.30 hours during the third day of continuous work. Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of reaction time, logical reasoning and short-term memory clearly showed better performance with both modafinil and amphetamine relative to placebo. Both modafinil and amphetamine maintained or increased body temperature compared to the natural circadian cycle observed in the placebo group. Also, from subject debriefs at the end of the study, modafinil elicited fewer side-effects than amphetamine, although more than the placebo group. Modafinil appears to be a good alternative to amphetamine for counteracting the debilitating mood and cognitive effects of sleep loss during sustained operations.

Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep.

Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night. Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups. This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.

Sleep inertia: best time not to wake up?

Sleep inertia is a brief period of inferior task performance and/or disorientation immediately after sudden awakening from sleep. Normally sleep inertia lasts < 5 min and has no serious impact on conducting routine jobs. This preliminary study examined whether there are best and worst times to wake up stemming from circadian effects on sleep inertia. Since the process of falling asleep is strongly influenced by circadian time, the reverse process of awakening could be similarly affected. A group of nine subjects stayed awake for a 64-h continuous work period, except for 20-min sleep periods (naps) every 6 h. Another group of 10 subjects stayed awake for 64 h without any sleep. The differences between these two groups in performance degradation are expected to show sleep inertia on the background of sleep deprivation. Sleep inertia was measured with Baddeley's logical reasoning task, which started within 1 min of awakening and lasted for 5 min. There appeared to be no specific circadian time when sleep inertia is either maximal or minimal. An extreme form of sleep inertia was observed, when the process of waking up during the period of the circadian body temperature trough became so traumatic that it created "sleep (nap) aversion." The findings lead to the conclusion that there are no advantages realized on sleep inertia by waking up from sleep at specific times of day.

Health effects of sleep deprivation.

This report provides information supporting the conclusion that sleep deprivation produces only very small biomedical effects. It nonetheless concludes that chronic partial sleep deprivation may contribute to gastrointestinal disorders, cardiovascular disease, and other medical conditions that occur more often in shiftworkers than in permanent dayworkers.

Decrements in logical reasoning performance under conditions of sleep loss and physical exercise: the factor of sentence complexity.

Baddeley's Logical Reasoning Test was used in a series of Sustained Operations (SUSOP) studies involving 100 US Marine Corps enlisted subjects, to assess the effects of sleep loss and long-term physical exercise on the ability to process complex information. The percent correct answers to the eight Logical Reasoning sentence types involving different voice (active vs passive), use of negatives, and outcome (true vs false) were analyzed over three days across three levels of exercise and rest conditions in the seven studies. A multivariate analysis of variance indicated no differences on the baseline day among the seven studies. Analyses on the baseline day and throughout the next two continuous workdays (CWs) showed consistently higher percent correct for the actively worded than for the passively worded sentences. The sleep loss over the two CWs resulted in a significant decrease in percent correct for the statements which had active wording. Sleep loss had no effect on statements with passive wording. There were no differences in comprehension between groups which had different rest conditions (no rest, 3- or 4-hr. nap, 8-hr. sleep) between the two CWs for any of the sentences; and there was no recovery from prerest to postrest. Fatigue due to exercise during either CW had no effect on comprehension for any of the sentence types. The sleep loss effects on comprehension seem due to a lessening of the attention given to those more simple sentences in active voice, whereas increased arousal may have been elicited by the more complex sentences in passive voice. The increased attention to the passive statements may have overcome the effects of sleep loss. The present study shows the usefulness of analyzing responses to the logical reasoning test by sentence complexity for indicating selective cognitive changes in the processing of information.

REM-NREM cycle in the cat may be sleep-dependent.

The periodicity of the rapid eye movement-nonrapid eye movement (REM-NREM) cycle in real time versus compressed sleep was determined by autocorrelation, computed on the sequence of sleep stages in recordings from spontaneously sleeping cats. The resulting autocorrelation function was correlated to damped cosine waves, and the highest squared correlation coefficient (r2) was taken as indicating the most likely periodicity in the data entered for each animal. The periodicity of REM sleep was stronger (significantly higher r2) in the compressed sleep data than in the real-time data, indicating sleep dependency of the REM-NREM cycle. The REM-NREM cycle lengths determined by the autocorrelation technique were not significantly different for the real-time and compressed sleep data. The REM sleep episode interval, defined as the average interval between the start of successive REM sleep episodes, was significantly shorter for real-time sustained sleep than the cycle lengths as determined by the autocorrelation technique. A model is proposed which explains this phenomenon as due to fragmentation of REM sleep within the time periods with high probability for REM sleep. When such fragmentation occurs, the average REM sleep episode interval will not reflect an ultradian REM sleep periodicity.

Altered circadian periodicities in oral temperature and mood in men on an 18-hour work/rest cycle during a nuclear submarine patrol.

A group of nuclear submariners was studied to examine whether an 18-h routine (6-h on, 12-h off watch) during a 10-week submerged patrol affected the 24-h circadian rhythm in oral temperature, Thayer's activation, Mood 'Activity' (MA) and Mood 'Happiness' (MH). They were observed during three phases of the patrol: Phase 1, the beginning 8-day period; Phase 2, the middle of the voyage; and Phase 3, the last 7-8 day period. The group-synchronized 24-h rhythm in oral temperature disappeared during Phase 3. The group-synchronized 24-h rhythms in Thayer's activation and in MA and MH disappeared during Phases 2 and 3. A group-synchronized 18-h rhythm was not produced in any of the variables in any phase, except MH during Phase 2. Periodicity analysis of the individuals' data showed that a loss of 24-h rhythmicity in oral temperature was due not only to reduced circadian amplitude but also to a dispersion of Time of Peak (TOPs). Loss of 24-h rhythm in 'Activation', 'Happiness', and 'Activity' was predominantly due to a wider dispersion of TOPs. The 18-h routine did appear to exert a small modulating effect on rhythmic activity in the variables examined in this study. Since the sleep/wakefulness cycle was well entrained by the 18-h routine, the submariners experienced a spontaneous internal desynchronization between the activity cycle and the cycles or oral temperature and psychological states. The performance and health consequences of this chronic dyschronism have yet to be explored. We suggest further research to determine the usefulness of an index of synchronization among the physiological and psychological variables, and the relationship of the desynchronizing effects to performance.

Dynamic relation of sleep spindles and K-complexes to spontaneous phasic arousal in sleeping human subjects.

K-complexes unaccompanied by sleep spindles (K0-complexes) and isolated sleep spindles during stage 2, non-rapid eye movement (NREM) sleep were examined before and after transient activation phase (AP) and also pseudo-AP during human sleep to determine the relationship of K0-complexes and sleep spindles to APs. Sixteen sleep records obtained from 16 young adult males were scanned for isolated APs during stage 2 NREM sleep. One hundred APs and 62 pseudo-APs were identified and analyzed. The number of sleep spindles decreased and reached its minimum at the onset of APs, when an increase was observed in the number of K0-complexes. APs occurred when a decrease in sleep spindles was coupled with an increased incidence of K0-complexes, thus forming an antagonistic relation. A similar antagonism was observed between sleep spindles and slow waves. A working hypothesis was formulated to interpret a triad of sleep events: sleep spindles. K0-complexes, and slow wave sleep. Three kinds of sleep--REM, spindles-dominant, and slow-wave-dominant--are suggested as more useful classifications than the Rechtschaffen and Kales categories.

K-complexes and sleep spindles before transient activation during sleep.

Six subjects spent three consecutive nights in the sleep laboratory. Activation phases (PATs), spontaneous K-complexes, and sleep spindles were visually detected in sleep stages 2 and 3 for nights 2 and 3. The K-complex rate was significantly greater in the 10 sec prior to the PATs than at any other time spent in stage 2 or 3. K-complexes associated with sheep spindles occurred significantly less frequently during the epochs just preceding the PATs. In all subjects, there was a sharp increase of sleep spindles associated with K-complexes when PATs did not follow within 10 sec. These results suggest that spontaneous K-complexes and sleep spindles act antagonistically with respect to the occurrence of PATs. These two phasic events are significantly related to regulating the probability of occurrence of PATs in sleep stages 2 and 3; K-complexes may reflect an organismic state leading towards PAT, whereas sleep spindles may inhibit the occurrence of PAT.

An attempted validation study of the birthdate-based biorhythm (BBB) hypothesis.

The birthdate-based biorhythm (BBB) hypothesis was examined for utility as a predictor of human performance. Data from quizzes of 26 students taken periodically throughout a semester, and measures over 1 month of landing performance by seven pilots were analyzed by multiple regression/correlation methods. Regression equations were developed to test the correspondence between performance and cycle phases. A second analysis used a nonorthogonal least-square spectrum method to determine if the data contained any systemic rhythms in the intradian range. No significant results were obtained whcih would support the BBB hypothesis as a predictor of human performance. Also, no evidence was found to substantiate the existence of the three proposed BBB cycles.

The effects of flurazepam hydrochloride on brain electrical activity during sleep.

To further evaluate the effects of flurazepam on EEG during sleep, following 7 nights of placebo baseline, flurazepam (30 mg) was administered to 6 young adult poor sleepers for 10 additional nights while 6 other young adult poor sleepers continued to receive placebo capsules in a double-blind paradigm. Three placebo follow-up nights were recorded 2--3 weeks post-treatment. Twelve good sleepers received only placebo capsules for the first 7 nights. Delta waves, 0.5--2 c/sec, and sleep spindles were counted on-line by a phasic detector. Delta activity was also analyzed off-line by PDP-12 computer for only the first 4 h of sleep and involved a comparison over stages of sleep. Click-evoked K-complexes during NREM sleep were analyzed for 6 good sleepers and 11 poor sleepers. Repeated use of flurazepam caused a gradual decrease in delta amplitude and count, and a gradual increase in sleep spindle rate. The decrease in delta amplitude was seen in all sleep stages, but the decrease was significant only during SWS and stage 2. The decrease in delta amplitude was significant by the 3rd drug night, but the rate of amplitude decrease tended to slow with continued treatment. The decrease in delta count was less pronounced and more gradual over drug nights than the rate of decrease in amplitude. Flurazepam also significantly reduced evoked K-complex amplitude but did not affect latency. Sleep spindle rate was significantly increased by drug night 5. Results of this study indicate that the reduction of SWS with flurazepam during the initial drug nights is due primarily to the decrease in delta amplitude, but, with continued use, the decrease in delta count also contributes to the decrease in stage 4 sleep.

Circadian variation in performance, subjective sleepiness, sleep, and oral temperature during an altered sleep-wake schedule.

The effect of an altered sleep-wake schedule on the interrelation of oral temperature, performance, and sleepiness was studied in 38 male Naval volunteers who maintained a 60 min treatment--160 min testing schedule for 40 consecutive hrs. During the 60 min treatment portion of each epoch, 8 subjected napped, 10 subjects exercised, and 20 subjects rested in bed. Sleep measures (for the nap subjects), oral temperature, performance on several tests, and Stanford Sleepiness Scale ratings were obtained at 10 equidistant intervals throughout the 40-hr period. Within-subject correlations showed that minimum oral temperature was significantly associated with maximum nap sleep time, errors on a vigilance task, and sleepiness ratings. In the nap subjects, errors and sleepiness ratings were highest following naps with high total sleep time, suggesting that sleep was detrimental to immediately subsequent performance and alertness. The distribution and interrelation of temperature, errors, and sleepiness, however, was similar in the three groups; this indicated that the synchronous circadian variation in these measures was responsible for the apparent detrimental effect of sleep in the nap subjects. When the diurnal effect was removed by holding time of day constant, the correlations among the variables fell to near-zero, indicating no causal relationship among the variables independent of the circadian rhythm.