Boris Perras

Sleep Enhances the Human Antibody Response to Hepatitis A Vaccination

Objective The common belief that sleep supports immune defense has received surprisingly little direct experimental support. The antibody response to vaccination provides a valid tool to assess the influence of sleep on adaptive immune functioning in humans, which is also clinically relevant. Methods Two groups of healthy humans (N = 19) not previously infected with hepatitis A virus (HAV) were studied. On the night after primary vaccination with inactivated HAV, which took place at 0900 hours, one group had regular sleep. The other group stayed awake, and did not sleep before 2100 hours the following day. HAV antibody titers were measured repeatedly until 28 days after vaccination. Plasma hormone concentrations and white blood cell (WBC) subset counts were determined on the night and day after vaccination. Results Subjects who had regular sleep after vaccination, displayed a nearly two-fold higher HAV antibody titer after 4 weeks than subjects staying awake on this night (p =.018). Compared with wakefulness, sleep after vaccination distinctly increased release of several immune-stimulating hormones including growth hormone, prolactin, and dopamine (p < .01). Concentrations of thyrotropin, norepinephrine, and epinephrine were lowered by sleep (p < .02), whereas sleep only marginally influenced WBC subset counts. Conclusions Data suggest that sleep compared with sleep deprivation on the night after vaccination improves the formation of antigen-specific immune defense as reflected by antibody production in humans. Sleep presumably acts by inducing a hormonal environment in secondary lymphoid tissues, enhancing lymphocyte proliferation and differentiation and finally antibody synthesis. Results underscore the importance of sleep for immunocompetence.

Effects of Cortisol Suppression on Sleep-Associated Consolidation of Neutral and Emotional Memory

BACKGROUND Previous research indicates that hippocampus-dependent declarative memory benefits from early nocturnal sleep, when slow-wave sleep (SWS) prevails and cortisol release is minimal, whereas amygdala-dependent emotional memory is enhanced through late sleep, when rapid eye movement (REM) sleep predominates. The role of the strong cortisol rise accompanying late sleep for emotional memory consolidation has not yet been investigated. METHODS Effects of the cortisol synthesis inhibitor metyrapone on sleep-associated consolidation of memory for neutral and emotional texts were investigated in a randomized, double-blind, placebo-controlled study in 14 healthy men. Learning took place immediately before treatment, which was followed by 8 hours of sleep. Retrieval was tested at 11 am the next morning. RESULTS Metyrapone suppressed cortisol during sleep and blocked particularly the late-night rise in cortisol. It reduced SWS and concomitantly impaired the consolidation of neutral texts. Emotional texts were spared from this impairing influence, however. Metyrapone even amplified emotional enhancement in text recall indicating amygdala-dependent memory. CONCLUSIONS Cortisol blockade during sleep impairs hippocampus-dependent declarative memory formation but enhances amygdala-dependent emotional memory formation. The natural cortisol rise during late sleep may thus protect from overshooting emotional memory formation, a mechanism possibly pertinent to the development of posttraumatic stress disorder.

Sleep and endocrine changes after intranasal administration of growth hormone-releasing hormone in young and aged humans

Systemic administration of growth hormone-releasing hormone (GHRH) has been found to improve human sleep in previous studies. Here we examined effects of GHRH on endocrine function and sleep after intranasal administration, a method which based on previous studies appears to enable a direct effect of peptides on brain function. Also, it was hypothesized that elderly humans displaying deficient GH release and sleep, benefit from GHRH administration more than young subjects. A study was performed according to a double-blind cross-over design. Each of 12 young and 11 old healthy men were intranasally administered with 300 micrograms GHRH (vs. placebo) 30 min before bedtime at 23:00 h. Sleep was recorded polysomnographically until 07:00 h and blood was collected in 15 min intervals for determination of cortisol and GH. Apart from the well-known age-related changes of hormonal secretion and sleep, intranasal GHRH reduced cortisol nadir concentrations in the beginning of sleep (P < 0.05), and also reduced the sleep-induced elevation in GH concentrations during early sleep. Moreover, results indicated that after intranasal administration GHRH increased rapid-eye-movement (REM) sleep and slow wave sleep (SWS), with this influence concentrating on the second half of sleep time. Effects of GHRH did not depend on the subjects age. We conclude that there is a coordinate influence of intranasal GHRH on the central nervous regulation of sleep processes and of hypothalamic-hypophysiotropic secretory activity in both young and elderly men. The effects may mimic the dual neuronal and endocrine function of hypothalamic GHRH activity.

Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders

The nose provides an effective way for delivering neuropeptides to the central nervous system, bypassing the blood-brain barrier and avoiding systemic side effects. Thereby intranasal neuropeptide administration enables the modulation of central nervous signaling pathways of body weight regulation and cognitive functions. Central nervous control of energy homeostasis is assumed to rely on hypothalamic neuropeptidergic pathways that are triggered by the peripheral adiposity signals insulin and leptin conveying the amount of body fat to the brain. Melanocortins, including alpha-melanocyte stimulating hormone (alpha-MSH), are essential for inducing anorexigenic/catabolic effects, i.e. for inhibiting caloric intake and increasing energy expenditure. Insulin, in addition to its function as an adiposity signal, also influences memory formation. Here we present a series of studies on the intranasal administration of MSH/ACTH4-10, a melanocortin receptor agonist, and of insulin. Prolonged administration of MSH/ACTH4-10 induced weight loss in normal-weight, but not in overweight humans. Intranasal insulin reduced body fat and improved memory functions in the absence of adverse peripheral side effects. Our results may contribute to the future development of therapeutic strategies in disorders like obesity and cognitive impairments that derive from dysfunctions of central nervous neuropeptidergic pathways.

Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease.

Sir: Disturbances of pineal function are well known in critically ill humans [1], but it is unclear whether melatonin blood concentrations are related to severity of illness. We measured serum melatonin concentrations at 2 a.m. in the first night in hospital in 302 patients consecutively admitted to the medical ICU of the University Hospital in Lübeck, Germany. At the same time the Acute Physiology And Chronic Health Evaluation (APACHE) II score and Therapeutic Intervention Scoring System (TISS) were assessed. Serum melatonin concentrations were determined by enzyme-linked immunosorbent assay

Beneficial treatment of age-related sleep disturbances with prolonged intranasal vasopressin.

Disturbed sleep is common in the elderly and is characterized by disordered sleep architecture with reduced time spent in slow wave sleep (SWS) and in rapid eye movement (REM) sleep. At present, no treatments are available to fully compensate for these disorders. In the elderly, vasopressin content is decreased at various brain sites. Investigating the effects of a 3-month intranasal vasopressin administration on sleep and cognitive functions in two elderly subjects in a foregoing pilot study, the authors found that the most pronounced influence of the peptide was a marked increase in SWS. This placebo-controlled, double-blind, randomized study examined the influences of a 3-month period of daily intranasal vasopressin treatment (20 IU before bedtime and after awakening) on nocturnal sleep in 26 healthy elderly subjects (mean age, 74.2 years). Intranasal treatment of vasopressin increased (1) the total sleep time, on average, by 45 minutes (p < 0.002); (2) time spent in SWS by 21 minutes (p < 0.025); and (3) time in REM sleep in the second half of the night by 10 minutes (p < 0.01). Vasopressin promotes sleep time and improves sleep architecture after prolonged intranasal administration in elderly subjects, although scores of subjective sleep quality did not change. Results suggest that age-related deterioration of sleep architecture can benefit from intranasal treatment with vasopressin. But a potential use in clinical settings will also depend on demonstrating improved subjective sleep quality, which remained unaffected by vasopressin in this study of elderly subjects.

Verbal memory after three months of intranasal vasopressin in healthy old humans.

In animals, evidence has been accumulated that vasopressin (VP) improves learning and memory. In humans, this effect was not consistently demonstrated, and attempts to restore age-related memory deficits by VP also remained inconsistent. Assuming that in old subjects a beneficial effect on memory occurs only after prolonged treatment with VP, we conducted a study in 26 healthy elderly persons receiving 40 IU of VP for three months through the intranasal route. The trial was randomized, placebo-controlled and held double-blind. Memory was assessed by the Auditory Verbal Learning Test (AVLT) requiring the subject to learn repeatedly presented lists of 15 words. Results demonstrated no general effect of long-term treatment with VP on memory in aged humans. However, recall of an interfering word list was improved, indicating a diminished proactive interference by the peptide. Additionally, VP influenced recall depending on the serial position of an item: it improved the primacy effect (i.e. recall of the first words of a list) and impaired the recency effect. This result may indicate an improved semantic encoding (i.e. a primary effect on processes of attention) after long-term administration of VP.

Changes in Immune Cell Counts and Interleukin (IL)-1β Production in Humans after a Somnogenically Active Growth Hormone-Releasing Hormone (GHRH) Administration

Growth hormone-releasing hormone (GHRH) has been shown to enhance slow-wave sleep (SWS) and non-rapid eye movement sleep in animals and humans. In animals the somnogenic effect of interleukin (IL)-1beta appears to be mediated by GHRH. Neuroimmunological interactions in sleep are most frequently studied in humans by sleep deprivation or by cytokine administration. The present study, in contrast, investigates in humans the effect of enhanced sleep through GHRH administration on selected immune parameters. Results reveal that a single intravenous bolus of 50 microg GHRH which enhanced SWS stage 4 in the first half of the night suppressed circulating suppressor T cell (CD3+/CD8+) numbers, with a similar tendency for B cells (CD19+) and suppressed mitogen-stimulated IL-1beta production. When the same amount of GHRH was administered distributed across five repetitive boluses of 10 microg GHRH within 1 h, neither corresponding sleep nor immune parameters were changed significantly compared to placebo. These data suggest that GHRH can modulate immune functions through brain mechanisms which are also involved in the regulation of sleep.

Sleep and Signs of Attention During 3 Months of Intranasal Vasopressin: A Pilot Study in Two Elderly Subjects

Prominent features of aging include a decrease of attention abilities and loss of sleep. Although acute effects of vasopressin (VP) on these functions in the elderly remained inconsistent, beneficial effects of the peptide may develop only with subchronic treatment, which so far has not been tested. This pilot study examined the changes in: i) event-related brain potentials (ERPs) during an attention task, ii) mood, and iii) nocturnal sleep in two healthy elderly subjects during a 3-month period of VP treatment (40 IU/day). The period of VP treatment was preceded and followed by 4-week periods of placebo treatment. ERPs and mood were not consistently affected by VP. However, unexpectedly, VP improved sleep by markedly enhancing nocturnal slow-wave sleep (SWS, p < 0.05). These findings indicate that effects of subchronic treatment with VP involve mechanisms different from those mediating acute effects.

Improvement of sleep and pituitary-adrenal inhibition after subchronic intranasal vasopressin treatment in elderly humans.

Subchronic intranasal treatment with argininevasopressin (AVP) has been shown to exert a strong ameliorating effect on sleep and slow wave sleep (SWS) deficits in elderly. However, AVP is also a potent stimulus of the pituitary-adrenal stress system, which is usually inhibited during early, SWS-rich sleep. A disinhibition of pituitary-adrenal activity during sleep is correlated with aging and is considered a pathologic factor contributing to various age-related diseases. Here, we examined whether the beneficial effect of prolonged intranasal AVP administration on sleep in aged would be associated with a concomitant decrease in pituitary-adrenal inhibition and effects on other neuroendocrine features of sleep. Twenty-six healthy elderly (mean 72.9 yr) with mild sleep complaints were investigated in a placebo controlled double-blind study. One group was treated daily each morning and evening with intranasal AVP (2×20 IU) for 10 weeks, the other received placebo. During polysomnographical recordings taken at the beginning and end of the treatment period, blood was sampled every 15 min. Intranasal AVP increased SWS on average by +21.5 min (p<0.02). The effect persisted on the night after acute withdrawal of the peptide treatment with no rebound occurring. Notably, rather than increasing pituitary-adrenal activity, AVP decreased the early sleep cortisol nadir on average by 0.5 μg/dl (p<0.05). AVP did not induce any measurable changes in fluid balance or cardiovascular activity. Overall, results indicate a promoting effect of AVP on SWS in aged accompanied by a beneficial rather than impairing influence on the neuroendocrine pattern of sleep.