Sleep latency measures of caffeine effects during sleep deprivation

Studies of stimulants during sleep deprivation have used performance assessment batteries (PABs) and occasionally the multiple sleep latency test (MSLT) as measures. Another type of sleep latency test, the maintenance of wakefulness test (MWT), assesses ability to remain awake without assistance, rather than ability to go to sleep. The MWT previously has not been used in studies of stimulants during sleep deprivation. This study of caffeine during 64 h without sleep included a PAB, the MSLT, and a single MWT trial per day. The PAB and the MSLT were sensitive to caffeine effects during the first 24 h without sleep. The MWT demonstrated that caffeine improved ability to remain awake even after 2 nights of sleep deprivation. Ability to go to sleep and ability to stay awake during sleep deprivation appear to be affected differently by caffeine. PAB testing may fail to detect this stimulant effect because technicians prevent subjects from nodding off during PAB testing, an external support not available to subjects during the MWT and also not available in many real-world work environments. The MWT was more sensitive to stimulant amelioration of sleep-deprivation effects. The findings need to be validated with MWTs at other times of day and with other stimulants.     

The effect of dietary caffeine manipulation on blood caffeine, sleep and disturbed behaviour

ABSTRACT. The effect of withdrawal of caffeine from the diet of a group of highly disturbed severely retarded adult patients was studied. Two weeks with drawal produced no improvement in sleep pattern or behaviour, but re-introduction of normal diet was accompanied by a highly significant increase ( P <0.001) in ward disturbance ratings.     

Amygdala kindling effects on sleep and memory in rats

Sleep disturbances accompany the development of amygdaloid-kindled seizures in cats. Some of these sleep deficits resemble those seen in aged rats; these latter changes in sleep patterns are correlated with memory impairments in the aged animals. In the present study, we examined the hypothesis that sleep deficits after kindling may be related to memory impairments. Rats were kindled for 4 weeks (2-2.5 weeks after stage 5 seizures) and were then allowed a one week recovery period. Sleep patterns were assessed through-out the kindling and recovery periods. The animals were then trained on an inhibitory avoidance apparatus and tested for retention 24 h later. Only transient sleep changes occurred during the development of kindling (to stage 5 seizures). However, continued kindling resulted in significant reductions in several sleep measures which remained depressed for at least one week after the termination of the kindling trials. As a group, kindled rats were impaired in retention of the inhibitory avoidance learned response. In kindled animals, retention performance was significantly correlated with total paradoxical sleep, the ratio of paradoxical/total sleep, and paradoxical sleep, the ratio of paradoxical/total sleep, and paradoxical sleep bout duration. These correlations are consistent with the view that deficits in paradoxical sleep may be related to deficits in some forms of memory.     

Recovery after prolonged sleep deprivation: residual effects of slow-release caffeine on recovery sleep, sleepiness and cognitive functions

A long work schedule often results in sleep deprivation, sleepiness, impaired performance and fatigue. We investigated the residual effects of slow-release caffeine (SRC) on sleep, sleepiness and cognitive performance during a 42-hour recovery period following a 64-hour continuous wakefulness period in 16 healthy males, according to a double-blind, randomised, placebo-controlled, crossover study. Three hundred milligrams of SRC or placebo was given twice a day at 21:00 and 9:00 during the first 48 h of wakefulness. Recovery sleep was analysed with electroencephalography (EEG) and wrist actigraphy, daytime sleepiness with continuous EEG, sleep latency tests and actigraphy and cognitive functions with computerized tests from the NATO AGARD STRES battery. Both drug groups exhibited almost the same sleep architecture with a rebound of slow-wave sleep during both recovery nights and of REM sleep during the second night. Wakefulness level and cognitive functions were similarly impaired in both groups on the first day of recovery and partially returned to baseline on the second. To conclude, SRC appears to have no unwanted side-effects on recovery sleep, wakefulness and cognitive performance after a long period of sleep deprivation and might therefore be a useful choice over other psychostimulants for a long work schedule.     

The effect of caffeine reduction on sleep quality and well-being in persons with HIV

OBJECTIVES: With reports of high rates of sleep disruption in Human Immunodeficiency Virus (HIV) + persons, this study tested whether there were differences in sleep quality and well-being between a group of HIV+ persons who reduced their caffeine intake from baseline by 90% or greater for 30 days (n=44) versus a group of HIV+ persons who continued their usual caffeine consumption (n=44). METHODS: Subjects were administered pre- and post-Pittsburgh Sleep Quality Index (PSQI), Perceived Well-being Scale-Revised (PWB-R) and MOS-HIV Health Survey instruments, with MOS-HIV summary scores used as a covariate. RESULTS: On ANCOVA analysis for sleep quality (F=14.032, P<.001), a 35% improvement in sleep among experimental subjects was identified. There was no significant difference between the two groups on ANCOVA analysis for well-being (F=0.111. P=.739). CONCLUSIONS: High levels of caffeine consumption may have an exacerbating effect on already prevalent HIV-related sleep pattern disturbances, and significant reductions of caffeine may improve sleep quality.     

The neuroprotective effects of caffeine in neurodegenerative diseases

Caffeine is the most widely used psychostimulant in Western countries, with antioxidant, anti‐inflammatory and anti‐apoptotic properties. In Alzheimer's disease (AD), caffeine is beneficial in both men and women, in humans and animals. Similar effects of caffeine were observed in men with Parkinson's disease (PD); however, the effect of caffeine in female PD patients is controversial due to caffeine's competition with estrogen for the estrogen‐metabolizing enzyme, CYP1A2. Studies conducted in animal models of amyotrophic lateral sclerosis (ALS) showed protective effects of A_2AR antagonism. A study found caffeine to be associated with earlier age of onset of Huntington's disease (HD) at intakes >190 mg/d, but studies in animal models have found equivocal results. Caffeine is protective in AD and PD at dosages equivalent to 3‐5 mg/kg. However, further research is needed to investigate the effects of caffeine on PD in women. As well, the effects of caffeine in ALS, HD and Machado‐Joseph disease need to be further investigated. Caffeine's most salient mechanisms of action relevant to neurodegenerative diseases need to be further explored.     

Modeling caffeine concentrations with the Stanford Caffeine Questionnaire: preliminary evidence for an interaction of chronotype with the effects of caffeine on sleep

ObjectiveTo examine the validity of a novel caffeine intake questionnaire and to examine the effects of caffeine on sleep in college students.MethodsOne-week, ad libitum behavior of 50 university students (28 female, 22 male; aged 20.9 ± 1.78 years) was examined with sleep logs, wrist actigraphy, and a novel daily questionnaire assessing caffeine intake at different times of day. Saliva samples were collected for caffeine assessment (questionnaire validation) and DNA extraction, and for analysis of a single nucleotide polymorphism in the adenosine receptor 2A (ADORA2A) gene.ResultsThe caffeine questionnaire was able to accurately predict salivary concentrations of caffeine (R² = 0.41, P < 0.001). Estimations of integrated salivary caffeine concentration during sleep were correlated with wake after sleep onset (WASO) most strongly in morning-type individuals (R² = 0.49; P < 0.001, ANOVA), less so in intermediate chronotypes (R² = 0.16; P < 0.001, ANOVA), and not significantly in evening-types (R² = 0.00098; P = 0.13, ANOVA). Using multivariate modeling methods we found that the ADORA2A genotype did not moderate the effects of caffeine on WASO, but did independently alter WASO such that those with the CC genotype had nearly three-times as much WASO as those with CT or TT.ConclusionsOur questionnaire was able to accurately predict salivary caffeine concentrations and helped to describe a novel relationship between the effects of caffeine on sleep and genotype and chronotype.     

The effects of modafinil, caffeine, and dextroamphetamine on judgments of simple versus complex emotional expressions following sleep deprivation

Cognitive abilities such as vigilance, attention, memory, and executive functioning can be degraded significantly following extended periods of wakefulness. Although much evidence suggests that sleep-loss induced deficits in alertness and vigilance can be reversed or mitigated by stimulants such as caffeine, it is not clear how these compounds may affect other higher level cognitive processes such as emotional perception and judgment. Following 47 h of sleep deprivation, the study examined the effect of three stimulant medications (modafinil 400 mg, dextroamphetamine 20 mg, caffeine 600 mg) or placebo on the ability of 54 healthy participants to discriminate and label simple emotional expressions versus complex affect blends (created by morphing photographs of two different affective facial expressions). For simple affective faces, neither sleep loss nor stimulant medications made any difference on the accuracy of judgments. In contrast, for complex emotion blends, all three stimulant medications significantly improved the ability to discriminate subtle aspects of emotion correctly relative to placebo, but did not differ from one another. These findings suggest that all three stimulant medications are effective at restoring some aspects of subtle affective perception.     

Acute cocaine effects in paradoxical sleep deprived male rats

Cocaine is a psychomotor drug known to cause behavioural alterations. This study was conducted to characterize behavioural response to acute cocaine injection (7 mg/kg, ip) in paradoxical sleep deprived (PSD) male rats since sleep deprivation is also associated with several behavioural alterations. Cocaine or vehicle was administered to rats at the end of a 4-day period of sleep deprivation, and in home-cage control animals. Cocaine administration in control and PSD rats induced a significant increase in stereotyped behaviour in relation to saline-injected rats. PSD induced significant but heterogeneous effects in animals by increasing grooming while it had effect neither on stereotyped behaviours, locomotion nor on anxiety-like behaviours but significantly decreased rearing behaviour. PSD potentiates the action of cocaine on stereotyped behaviours suggesting supersensitivity of dopaminergic receptors. Thus, the present study indicated that the behavioural effects of cocaine could be modified by PSD. This in turn may have relevant implications in the cocaine effect in abusers under sleep deprived condition.     

The effects of gamma-hydroxybutyrate on sleep.

Sodium gamma-hydroxybutyrate (GHB) is a remarkably safe and nontoxic hypnotic agent which is reported to be free of addicting properties. It is also a normal metabolite of the mammalian nervous system. We examined its effects on the sleep-EEG of eight patients with histories of impaired sleep, as a prelude to a more detailed study of its clinical potential. Sleep induced with GHB was indistinguishable subjectively from natural sleep as well as by behavioral and electroencephalographic criteria. Unlike most synthetic hypnotics, GHB increased delta sleep and did not suppress REM sleep. It shortened the REM sleep latency and shifted REM sleep into the first third of the night. On one occasion it induced a sleep onset REM period which was experienced as an attack of sleep paralysis. Withdrawal was simple; there was no REM sleep rebound and sleep patterns immediately returned to their pre-drug form. Its major clinical drawback was its short duration of action: its hypnotic effect lasting only 2 to 3 hr. We suggest that GHB may serve as the prototype for a new class of hypnotic compounds derived from natural sources and capable of activating the neurological mechanisms of normal human sleep.     

The effects of pentylenetetrazol, chlordiazepoxide and caffeine in rats tested in the elevated plus-maze depend on the experimental illumination

The so-called anxiolytic and anxiogenic drugs are considered to cause, respectively, increases and decreases in plus-maze open arm exploration, without modifying locomotor activity occurring in the closed arms in an elevated plus-maze when the animals are tested in an illuminated environment. Simply testing animals in the dark also increases open arm exploration, which may be interpreted as an anxiolytic effect. We investigated the effects of two GABAergic drugs, pentylenetetrazol (10 and 20 mg/kg) and chlordiazepoxide (1.5 and 3 mg/kg), and one non-GABAergic drug, caffeine (10 and 30 mg/kg) on anxiety levels of rats tested in the elevated plus-maze under two illumination conditions, light or dark. All animals explored more the open arms in the dark. In the light, pentylenetetrazol decreased open arm exploration while chlordiazepoxide had the opposite effect. Neither pentylenetetrazol nor chlordiazepoxide had any effect in the dark. Caffeine, increased open arms exploration in both illumination conditions. These results indicate that light triggers aversion, a response mediated by GABA since the GABAergic drugs, but not caffeine, were ineffective when the rats were tested in the dark.     

The effects of acute sleep restriction and extension on sleep efficiency

This study employed a repeated measures design to assess the relationship between sleep efficiency and time-in-bed (TIB). Fourteen subjects underwent three TIB conditions: (5 hour, 8 hour, and 11 hour), which were presented in a Latin Square design. Subjects slept a total of six nights (two nights per condition) while being monitored by a wrist actigraph to determine sleep time. Sleep efficiencies (sleep time/TIB) were analyzed with a two-way repeated-measures ANOVA. The main effect of night was not significant. The main effect of TIB and the interaction of nights and TIB were significant. In the 11-hour condition, sleep efficiency fell from night one to night two, and on night two both the 5-hour and the 11-hour conditions were significantly different from the 8-hour condition. Analysis of total sleep time (TST) yielded the same results with the addition of a significant night-to-night difference in the 5-hour condition. It was concluded that sleep efficiency systematically changes with an extension or restriction of TIB from 8 hour.     

Flurazepam and triazolam: dose-response and time-response evaluation on cat sleep

A window discrimination method is presented for the continuous monitoring of sleep-wakefulness cycles in cats. Window discrimination permits the recording of the frequency of firing of multiple units, while filtering out movement artifacts and low-level noise. Records of reticular formation multiple unit activity (MUA) and EMG from cats with chronically implanted electrodes were quantified by window discrimination and displayed on a strip chart recorder. The frequency of firing of large reticular multiple units was highest in states of high CNS excitation (i.e., REM), and the lowest in states of low CNS excitation (i.e., SWS). Comparison of recording of reticular MUA by window discrimination and rectification-integration indicated that sleep-wakefulness states were more easily distinguished with the former method. The effects of flurazepam, 1.25-5 mg/kg i.p., and triazolam, 0.01-0.05 mg/kg i.p., on reticular MUA were observed for 24-72 h of continuous recording. Both benzodiazepines depressed reticular MUA by up to 50% in a dose-related fashion. Flurazepam was effective for 72 h or more, and triazolam for 24-48 h. Flurazepam was also much longer lasting than triazolam when administered for 3 days at 24 h intervals. As evidence by our evaluation of flurazepam and triazolam, it appears that evaluation of the effects of sedative-hypnotics on the CNS excitation level of the cat, and the duration of these effects, can be readily performed and these results generalized to the clinical experience. This should prove useful in the evaluation of novel sedative-hypnotics.     

Distinct effects of acute and chronic sleep loss on DNA damage in rats

The aim of this investigation was to evaluate genetic damage induced in male rats by experimental sleep loss for short-term (24 and 96 h) and long-term (21 days) intervals, as well as their respective recovery periods in peripheral blood, brain, liver and heart tissue by the single cell gel (comet) assay. Rats were paradoxically deprived of sleep (PSD) by the platform technique for 24 or 96 h, or chronically sleep-restricted (SR) for 21 days. We also sought to verify the time course of their recovery after 24 h of rebound sleep. The results showed DNA damage in blood cells of rats submitted to PSD for 96 h. Brain tissue showed extensive genotoxic damage in PSD rats (both 24 and 96 h), though the effect was more pronounced in the 96 h group. Rats allowed to recover from the PSD-96 h and SR-21 days treatments showed DNA damage as compared to negative controls. Liver and heart did not display any genotoxicity activity. Corticosterone concentrations were increased after PSD (24 and 96 h) relative to control rats, whereas these levels were unaffected in the SR group. Collectively, these findings reveal that sleep loss was able to induce genetic damage in blood and brain cells, especially following acute exposure. Since DNA damage is an important step in events leading to genomic instability, this study represents a relevant contribution to the understanding of the potential health risks associated with sleep deprivation.     

Differential effects of acute cold and footshock on the sleep of rats

Several studies have shown that 1 h of immobilisation stress during the rat's active period results in rebound of paradoxical (PS) and slow wave sleep (SWS). Since the effects of stress on behaviour and physiological parameters vary according to the stimulus, the present study sought to examine the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sleep pattern of rats submitted to 1 h of footshock, immobilisation or cold, or 18 h of PS deprivation (PSD). Stress sessions began between 0900 and 0930 h. Immediately after the end of the stress session, or at the corresponding time for controls, animals were blood sampled for determination of ACTH and corticosterone (CORT) plasma levels. In Experiment 2, animals were implanted with electrodes for basal and post-stress polysomnographic recording (6 h long). The results showed that all stressors produced an activation of the HPA axis; however, footshock induced the largest ACTH levels, whereas cold resulted in the highest CORT levels. In regard to the sleep data, immobilisation and PSD led to a rebound of SWS (+16.87% and +9.37%, respectively) and PS (+42.45% and +55.25%, respectively). Immobilisation, however, induced an increased number of PS episodes, whereas PSD resulted in longer PS episodes. Cold stress produced an exclusive rebound of SWS (+14.23%) and footshock promoted sustained alertness during the animal's resting period (+47.18%). These results indicate that different stimuli altered the sleep pattern in a distinct manner; and these alterations might be related to the state of the HPA axis activation.     

Effects of caffeine on electrophysiological and neuropsychological indices after sleep deprivation

Caffeine is regarded as a central nervous system (CNS) stimulant. The goal of this study was to analyze electrophysiological, motor, cognitive and behavioral changes produced by caffeine ingestion after sleep deprivation. Ten subjects were evaluated after sleep deprivation, comparing the ingestion of either 400 mg of caffeine or placebo, in a double-blind randomized study. The variables analyzed were: quantitative EEG, the event-related potential (ERP-P300) and cognitive responses. The most significant quantitative EEG results, which were characterized by moment x treatment interactions, were seen in alpha and theta relative power variables. A significant decrease in relative alpha and theta was observed in the caffeine group after sleep deprivation. In relation to caffeine stimulant effects, there were no significant differences in the other parameters.     

The effects of tones on PGO waves in slow wave sleep and paradoxical sleep

Ponto-geniculo-occipital (PGO) waves are macropotential waveforms occurring spontaneously during paradoxical sleep (PS) in the pons, the lateral geniculate body (LGB), and the occipital cortex of the cat. In our earlier work (6, 20) tones elicited waves in the LGB and the occipital cortex during both slow wave sleep (SWS) and PS that resembled PGO waves in form and amplitude. Using a limited and variable number of trials, we observed that these elicited waveforms, which we term elicited PGO waves (PGOE), seemed to decline rapidly in amplitude and probability during SWS but not during PS. The present two experiments served as a more rigorous test of the hypothesis that the rate of habituation of PGOE would be more rapid in SWS. In a first experiment seven cats were studied in up to four sessions in PS and four in SWS; each session consisted of 32 1000-Hz, 90-dB SPL tones lasting 90 ms. We found that (i) the number of PGOE was significantly greater in PS; (ii) the mean amplitude of the waves was greater in PS; (iii) the probability of eliciting a wave tended to decline faster in SWS, but some decline also occurred in PS; and (iv) on the first trial, PGOE were more easily produced in SWS. Results of a second experiment with five cats suggested that the decline in the probability of PGOE in PS was not accounted for by differences in the ease of eliciting them at different times into a PS episode. The role of the dorsal raphe nucleus (DRN) in modulating state-dependent differences in PGOE is discussed.     

A comparison of the effects of S-adenosyl-L-homocysteine on sleep in normal and pinealectomized rats

S-adenosyl-L-homocysteine (SAH) was administered to normal and pinealectomized rats previously implanted with electrodes for polygraphic recording. In normal rats, injected at 17.00 h, 7 mg/kg SAH induced a significant increase of paradoxical sleep (PS) during the night. When injected at 09.00 or 19.00 h, no effect was observed. In pinealectomized rats, SAH had no significant effect on PS amounts but seemed to resynchronize the PS rhythm. Thus, the pineal gland plays an important role in SAH effect. The results are discussed with reference to different mechanisms within the rat pineal gland and a possible implication of beta-adrenergic receptors.     

Effects of caffeine on heart rate and QT variability during sleep

Administration of caffeine in the evening produces poor sleep. Patients with insomnia have characteristic electrocardiogram (ECG) changes, including increased heart rate (HR), increased sympathetic activity, and decreased parasympathetic activity. Fifteen young adult normal subjects slept in the laboratory for several nights prior to randomization into a caffeine protocol where subjects received caffeine 400 mg 30 min prior to one night of sleep and placebo randomly prior to another night. ECG was sampled at a rate of 500 Hz and recorded onto a PC. Data samples of 256-s periods of the ECG trace were taken from wake (before sleep), stage II, and REM for placebo and caffeine conditions. A peak detection algorithm was used to identify the R-R intervals (in milliseconds) from the ECG. A common QT variability algorithm was used to find the QT interval for each beat using the time-stretch model. The powers for HR and QT series were integrated in the bands of LF (low frequency: 0.04-0.15 Hz) and HF (high frequency: 0.15-0.5 Hz) bands. There was a significant caffeine by sleep stage interaction for LF/HF ratios (F = 4.0; df = 2, 18; P = .04). LF/HF ratios were significantly higher during REM following caffeine administration. There was also a significant caffeine by sleep stage interaction for QTvi (QT variability normalized for mean QT interval divided by HR variability normalized for mean HR; F = 5.6; df = 2, 12; P = .02). QTvi was also significantly higher during REM following caffeine administration. The higher LF/HF ratios and QTvi during REM are most likely due to the sympathetic effects of caffeine. These findings suggest that excessive caffeine intake may result in adverse cardiovascular events in vulnerable subjects.     

The effects of caerulein on nocturnal, sleep

1. Caerulein, a decapeptide chemically related to cholecystokinin octapeptide, was examined polysoninographically for its effect on nocturnal sleep in healthy volunteers.

2. The subjects were 6 males (20–24 years of age). Either a placebo (saline) or caerulein 0.6 μg/kg was administered intramuscularly to volunteers at 23:00.

3. Polysomnograms were then recorded from 23:00 till 06:30.

4. Little variation in sleep period time, total sleep time, sleep efficiency index, sleep latency, or REM sleep latency in the drug night were found as compared to the control night values.

5. The percentage of REM stage sleep increased significantly (P < 0.01) on the drug administered night, whereas the change in the percentages of each of the other stages was not significant.

6. The REM density of the vertical eye movements tended to increase on the drug night, but the density of the horizontal eye movements showed no change.

7. There were no changes in the spontaneous GSRs in either vola or dorsum manus.

8. As caerulein shows alpha-1 adrenergic receptor blocker activity, it is suggested that caerulein may increase REM sleep by affecting the central noradrenergic neurons.