Cameron J. van den Heuvel

Thermoregulation as a sleep signalling system

Temperature and sleep are interrelated processes. Under normal environmental conditions, the rhythms of core body temperature Tc and sleep propensity vary inversely across the day and night in healthy young adults. Although this relationship has drawn considerable interest, particularly in recent years, it is still not known whether this relationship is causative or merely coincidental. As somnogenic brain areas contain thermosensitive cells, it is possible that the sleep/wake cycle may be directly affected by thermoregulatory changes themselves. That is, that changes in temperature may trigger, either directly or indirectly, somnogenic brain areas to initiate sleep. There is now an emerging body of evidence from both physiological and neuroanatomical studies to indicate that this may indeed be the case. This paper will examine the literature relating to this relationship and propose a model where thermoregulatory changes provide an additional signal to the brain regions that regulate sleep and wakefulness. The model attempts to explain how temperature changes before and after sleep onset act in a positive feedback loop to maintain a consolidated sleep bout.

Urinary 6-sulfatoxymelatonin excretion and aging: New results and a critical review of the literature

Abstract: The apparent age‐related decline in melatonin production has been thought to continue in a secular manner across the lifespan. While it is clear that melatonin levels in children and adolescents are elevated compared to older individuals, the question of whether there is a sudden or gradual change has not been adequately addressed. In this study, we report the excretion of the melatonin metabolite, 6‐sulfatoxymelatonin in 253 subjects aged between 21 and 82 yr. The correlation with age was significant (r= ‐ 0.24; P < 0.05). When the data was analysed by ANOVA using 5‐yr age spans, there was a significant effect of age, but post hoc analysis indicated that after 25 yr of age there was no significant decline in excretion of the metabolite. Thus, although the oldest subjects excreted 36% less melatonin metabolite than the youngest, the decrease occurred at a very early age. In the second part of the study, we re‐evaluated the data from seven previous studies that measured plasma melatonin levels or metabolite excretion across a wide range of ages and 11 studies comparing young versus older subjects. Statistical analysis by ANOVA again suggested that the changes in melatonin occurring with age were essentially complete before 30 yr of age. The youngest subjects produced at the most twice the amount of melatonin as the oldest subjects. Finally, we evaluated the mean plasma melatonin levels in 144 groups of normal subjects reported in 137 separate publications with respect to age. Again, whereas there was a significant correlation with age, ANOVA showed that there was no difference between groups after 35 yr of age, and the oldest groups had levels that were only 43% of the youngest groups. We conclude that melatonin production is lower in older people, but that the change occurs very early in life, around 20–30 yr of age.

Daytime melatonin and temazepam in young adult humans: equivalent effects on sleep latency and body temperatures

1 As changes in core body temperature are generally associated with concomitant changes in sleep propensity, it is possible that the effects of hypnotic/soporific agents may be related to changes in thermoregulation. Therefore, to increase our knowledge of the mechanisms by which these agents exert their soporific effects, we compared the thermoregulatory and soporific effects of temazepam (20 mg per os (p.o.)) with those of melatonin (5 mg p.o.) when administered at 14.00 h to 20 young healthy adults (13 male, 7 female; age, 23·5 ± 0·4 years). 2 From 08.00 to 20.30 h, subjects lay in bed, and foot and rectal (Tc) temperatures were recorded. Sleep onset latency (SOL) was measured using 20 min multiple sleep latency tests, performed hourly from 11.00 to 20.00 h, during which time heart rate was recorded. 3 Compared with placebo, both melatonin and temazepam significantly reduced Tc (‐0·17 ± 0·02 and ‐0·15 ± 0·03 °C, respectively) and SOL (by 4·8 ± 1·49 and 6·5 ± 1·62 min, respectively). Although both treatments significantly increased heat loss, only melatonin demonstrated cardiac effects. Importantly, there was a temporal relationship between minimum SOL and the maximum rate of decline in Tc for both melatonin (r= 0·48) and temazepam (r= 0·44). 4 A possible role of thermoregulation in sleep initiation is suggested by the similar temporal relationship between Tc and SOL for two different classes of soporific agents.

Day‐time melatonin administration: Effects on core temperature and sleep onset latency

Significant hypothermic and hypnotic effects have been reported for melatonin at a wide range of doses. It has been suggested that this decrease in core temperature (Tc) following melatonin administration may mediate the observed increase in sleepiness. To test this, melatonin was administered to young adults during the day, and the concurrent effects on Tc and sleep onset latency (SOL) were recorded. Sixteen healthy males received either a 5 mg oral formulation of melatonin or placebo at 14.00 hours. Core temperature was recorded continuously. Sleep onset latency to stage 1 (SOL1) and stage 2 (SOL2) were recorded using an hourly multiple sleep latency test (MSLT). Compared with placebo, melatonin significantly decreased Tc 1.5 h after administration for 6 h. Between 15.00 and 18.00 hours, the drop in Tc was associated with a concurrent decrease in SOL1 and SOL2. Following administration mean SOL1 and SOL2 were reduced by 40 and 25%, respectively. In this study, daytime melatonin administration produced a significant decrease in Tc with a corresponding decrease in SOL. Taken together, these data are not inconsistent with the suggestion that melatonin may facilitate sleep onset via a hypothermic effect. In addition, this study provides support for the idea that melatonin may play a role in regulating circadian and/or age‐related variations in sleep/wake propensity. From a practical perspective, exogenous melatonin may be useful in the treatment of sleep disorders associated with increased nocturnal Tc.

Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatonin.

To examine the physiological role of melatonin in sleep, nocturnal melatonin secretion was suppressed using 100 mg oral atenolol in two studies. In Study 1, nocturnal sleep was recorded in 8 young men over 4 nights. Subjects received atenolol on one of the last 2 nights and showed significantly increased total wake time (TWT) and wakefulness after sleep onset (WASO), as well as decreased REM sleep and slow-wave sleep (SWS). When melatonin (total 5 mg) was given after atenolol on the other night, the changes in TWT, WASO, REM, and SWS were reversed. In Study 2, sleep onset latencies (SOL) and core temperature (Tc) of 10 young men were measured for 3 nonconsecutive nights. In a cross-over design, atenolol given on one night significantly suppressed urinary 6-sulphatoxymelatonin (6s-aMT) production and increased hourly measures of Tc and SOL relative to baseline night values. Oral melatonin (3 mg), administered after atenolol, reversed the changes in Tc and SOL. These results suggest that endogenous melatonin may assist in the maintenance of normal sleep architecture (Study 1) and also increase nocturnal sleep propensity by hypothermic effects (Study 2).

Adenotonsillectomy and neurocognitive deficits in children with Sleep Disordered Breathing.

Background Sleep Disordered Breathing (SDB) is a common childhood disorder that encompasses a range of sleep-related upper airway obstruction. Children with SDB demonstrate significant neurocognitive deficits. Adenotonsillectomy is the first line of treatment for SDB and whilst this improves respiratory disturbance, it remains to be established whether neurocognitive gains also result. Methods A total of 44 healthy snoring children aged 3–12 years awaiting adenotonsillectomy (SDB group), and 48 age and gender matched non-snoring controls from the general community, completed the study. All children underwent polysomnography and neurocognitive assessment at baseline and after a 6-month follow-up (after surgery in the snoring group). Our primary aim was to determine whether neurocognitive deficits in snoring children were significantly improved following adenotonsillectomy. Results Wide ranging neurocognitive deficits were found at baseline in SDB children compared to controls, most notably a 10 point IQ difference (P<.001) and similar deficits in language and executive function. Whilst adenotonsillectomy improved respiratory parameters and snoring frequency at 6 months post surgery, neurocognitive performance did not improve relative to controls. Conclusion Adenotonsillectomy successfully treated the respiratory effects of SDB in children. However, neurocognitive deficits did not improve 6-months post-operatively.

Inconsistent sleep schedules and daytime behavioral difficulties in school-aged children

OBJECTIVES Current recommendations for healthy sleep in school-aged children are predominantly focused on optimal sleep duration (9-11h). However, given the importance of routine for circadian health, the stability of sleep/wake schedules may also be important, especially for daytime behavioral functioning. We examined the relationship between short sleep duration, sleep schedule instability and behavioral difficulties in a community sample of Australian children. METHODS Children, aged 5-10 years (N=1622), without chronic health or psychological conditions, were recruited from primary schools in Adelaide, South Australia. A parent-report questionnaire was used to assess sleep/wake behavior. Behavioral functioning was assessed using the Strengths and Difficulties Questionnaire. RESULTS Most children met sleep duration recommendations with approximately 5% reporting <9h and 3% >12h. Weekly variability of bed and rise times >1h were reported in up to 50% of children. Multinomial regression analysis revealed sleep duration <10h, bedtime latency >60 min, and bed and rise time variability >60 min significantly increased the risk of scoring in the 95th percentile for behavioral sub-scales. CONCLUSIONS Inconsistent sleep schedules were common and, similar to short sleep duration, were associated with behavioral difficulties. Considering the lack of study in this area, further research is needed for the development of new recommendations, education and sleep health messages.

CHANGES IN SLEEPINESS AND BODY TEMPERATURE PRECEDE NOCTURNAL SLEEP ONSET :EVIDENCE FROM A POLYSOMNOGRAPHIC STUDY IN YOUNG MEN

Recent research has shown a close temporal relationship between the nocturnal decrease in rectal core temperature and the initiation of sleep. However, there is not yet a clear temporal relationship between changes in peripheral and core temperatures and nocturnal sleep onset. We recorded body temperatures in 14 adult males (age±SEM=22.1±0.6 y), who attended the sleep laboratory for an adaptation night and two counterbalanced experimental sessions. Subjects self‐selected lights‐out on one experimental night (the Habitual Sleep condition). To determine the relationship between body temperature changes and sleep onset, lights out was delayed until after 01.00 hours on the other experimental night (Delayed Sleep condition). Individual datasets in both conditions were expressed relative to the time of sleep onset in the Habitual Sleep condition only, so that they were aligned at identical clock times. Saliva samples confirmed that mean dim light melatonin onset (DLMO) occurred at 00.10±00.16 hours in the Delayed Sleep condition, which was after habitual sleep onset at 23.44±00.08 hours. Rectal core temperature (Tc) decreased significantly over time only in the Habitual Sleep condition ( P < 0.01). For the 20 min before habitual sleep onset, Delayed Sleep Tc was on average 0.1°C higher than Tc in the Habitual Sleep condition ( P < 0.01). The greater decline in Habitual Sleep Tc was associated with significantly increased peripheral hand and foot skin temperatures before sleep (both P < 0.05). Subjective sleepiness measures were higher in the Habitual Sleep onset condition from 150 min prior until sleep onset ( P < 0.01). From these results it is reasonable to infer that a sequence of thermoregulatory and sleep propensity changes occur before, but are associated with habitual sleep onset, as the changes are significantly attenuated if sleep is delayed.

Integrating the actions of melatonin on human physiology

Melatonin has a diverse range of physiological effects in humans. Reported effects include modulation of the sleep-wake, thermoregulatory, cognitive, cardiovascular and immune systems. While integrating these broad-ranging effects is difficult when current paradigms are used, the diverse effects of melatonin on human physiology may be better understood by shifting our theoretical perspective. Traditionally, research has treated melatonin as a classical hormone for which a defined effect in physiological systems and a mechanism of action can be elucidated. In this article, we suggest that it may be more appropriate to view melatonin as an evolutionally stable timing signal to which each species has adapted the timing of physiological processes. From this perspective, it appears that the physiological role of melatonin in humans falls into two categories. The first relates to the self-regulation of circadian timing by the suprachiasmatic nucleus-pineal complex. The second relates to the promotion of restorative or anabolic physiological processes. In humans, elevated melatonin levels have been associated with reduced core temperature, increased heat loss, decreased cardiovascular output, reduced alertness and enhanced immune responsiveness. Taken together, these changes suggest that melatonin may increase the propensity for physiological processes promoting nocturnal sleep or processes that occur during the sleep period.

Effect of Sustained Nocturnal Transbuccal Melatonin Administration on Sleep and Temperature in Elderly Insomniacs

Previous research has suggested a role for the pineal hormone melatonin in the control of the bodys sleep-wake and thermoregulatory systems. In the elderly population, there have been reports of decreased nighttime secretion of melatonin and suggestions that this may, in turn, be responsible for the increased incidence of sleep disorders reported by this age group. On this basis, it has been suggested that augmented nocturnal melatonin levels may improve sleep quality in age-related sleep disorders. Following screening assessments, 12 elderly (> 55 years) subjects with sleep maintenance insomnia were treated with either 0.5 mg transbuccal melatonin or a placebo for two sessions of 4 consecutive nights, at least 3 days apart. Subjects self-selected lights-out times, and sleep was assessed using standard polysomnographic (PSG) measures. Body temperature was measured continually from 2100 to 0700 h, and sleep quality was assessed from PSG variables measured. Nightly urine samples were assayed for the melatonin metabolite 6-sulfatoxy-melatonin (aMT.6S). Compared to the placebo, transbuccal melatonin administration significantly increased mean nocturnal aMT.6S excretion (mean ±SEM: 194.2 ± 16.5 vs. 42.5 ± 7.7 nmol). In addition, there was a significant reduction in core body temperature relative to the placebo condition (p < .05). However, sustained transbuccal melatonin treatment had no positive significant effect on any PSG measure of sleep quality. The results from the present study suggest that sustained nocturnal administration of melatonin, in the low pharmacological range, might be of limited clinical benefit in this subject population.