Elisabeth Friess

Heritability of Sleep Electroencephalogram

BACKGROUND Understanding the basis of sleep-related endophenotypes might help to pinpoint factors modulating susceptibility to psychiatric disorders. However, the genetic underpinnings of sleep microarchitecture in humans remain largely unknown. Here we report on the results of a classical twin study in monozygotic (MZ) and dizygotic (DZ) twin pairs examining the genetic effect on sleep electroencephalogram (EEG) composition. METHODS Polysomnographic recordings were obtained in 35 pairs of MZ (26.4 +/- 5.4 years, 17-43 years, 17 male pairs, 18 female pairs) and 14 same-gender pairs of DZ twins (22.1 +/- 2.7 years, 18-26 years, 7 male pairs, 7 female pairs). The EEG power spectra were generated on the basis of Fast Fourier transformations combined with conventional sleep parameters, according to standardized criteria. RESULTS We tested the genetic variance contributing to the observed overall variance of the sleep measures and found that the relative contributions of the delta, theta, alpha, and sigma frequency bands at central derivations were significantly correlated to the genetic background. In these frequency bands, MZ twins also showed within-pair concordance in spectral power that was significantly higher than that of DZ twins. CONCLUSIONS The broad overlap of EEG frequencies during non-REM sleep and wakefulness, which shows a significant genetic variance, supports the hypothesis of common neuronal mechanisms generating EEG oscillations in humans. Our findings strongly support the suitability of the spectral composition of non-REM sleep for defining endophenotypes.

The hypothalamic-pituitary-adrenocortical system and sleep in man

This review article summarizes the major findings about the interactions of human sleep structure and the hypothalamo-pituitary-adrenocortical (HPA) system under physiological and pathophysiological conditions, including studies that probe the sleep effects of systemically administered HPA hormones. Human sleep is regulated by a concerted action of various signal compounds acting at sleep-generating neurons whose central organization is not yet fully understood. During nocturnal sleep the endocrine system is remarkably active, the longest established finding being that growth hormone (GH) release is associated with the initiation of sleep and that there is a steep morning rise of cortisol (Weitzman et al., 1966; Takahashi et al., 1968). Moreover, the effects of exogenously administered corticosteroids and of their excessive endogenous release (e.g. Cushings disease) were recognized more than 20 years ago.

Steroid effects on central neurons and implications for psychiatric and neurological disorders

Acute and chronic stress as well as a number of psychiatric and neurological disorders are accompanied by profound disturbances of the HPA system. These neuroendocrine alterations act back on the central nervous tissue mainly via corticosteroids-affecting glucocorticoid and mineralocorticoid receptors. The major conclusions drawn from studies probing these receptors in clinical investigations are: (1) In many such conditions central corticosteroid receptors are weakened in their capacity to curtail spontaneous and stress-elevated corticosteroid levels; (2) the combined DEX-CRH test is the best neuroendocrine tool currently available for identifying HPA abnormalities in psychiatric patients; (3) in depression the decreased corticosteroid receptor capacity in transient, and antidepressants act through reinstatement of GR and MR function probably resulting in reduced hypothalamic CRH and AVP production; (4) several neurological disorders such as MS and HIV infection are often accompanied by altered HPA function, which has therapeutic implications; and (5) various corticosteroids, their biosynthetic precursors and their metabolites have differentiable effects on the sleep EEG, which can be attributed to their mode of action; specifically, steroids such as pregnenolone and DHEA most likely are produced in glia cells and act in a paracrine fashion at neurons, thus modifying the sleep EEG in humans in a manner that suggests their potential as memory enhancers.

Effects of pulsatile cortisol infusion on sleep-EEG and nocturnal growth hormone release in healthy men

SUMMARY  This study investigates the short‐term effects of pulsatile cortisol administrations upon sleep electroencephalogram (EEG) and spontaneous release of growth hormone (GH) in humans. Ten young healthy male volunteers received intravenous injections of either placebo or cortisol every 60 min between 17.00 hours and 06.00 hours (1 mg kg‐1 BW with a loading dose of 20% starting at 17.00 hours, followed by a dose of 6% every hour until 06.00 hours). The amount of rapid eye‐movement (REM) sleep was significantly reduced (placebo: 19.9 ± 1.8; cortisol: 12.2 ± 1.5%; P < 0.05), whereas the time spent in slow‐wave sleep (SWS) was significantly increased (placebo: 9.4 ± 1.6; cortisol: 13.9 ± 1.9%; P < 0.05). The SWS‐promoting effect was most prominent during the first hours of sleep, but tended to persist also during the second half of the night. The pulsatile cortisol administration augmented the total amount of plasma GH concentrations (mean area under the time course curve, AUC, placebo: 3.2 ± 0.5; cortisol: 4.4 ± 0.6 [ng × 1000 × ml min‐1]; P < 0.05) due to an increase of GH release before sleep onset, and during the second half of the night, while the GH surge at sleep onset remained unchanged.

Effects of Hormones on Sleep

Administration of hormones to humans and animals results in specific effects on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies with pulsatile administration of various neuropeptides in young and old normal controls and in patients with depression suggest they play a key role in sleep-endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute to sleep-endocrine aberrations during normal ageing and acute depression. In addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly, somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH, probably by feedback inhibition of CRH. Neuroactive steroids exert specific effects on the sleep EEG, which can be explained by γ-aminobutyric acidA receptor modulation.

Microstructure of the non-rapid eye movement sleep electroencephalogram in patients with newly diagnosed Parkinson's disease: Effects of Dopaminergic treatment

We investigated non‐rapid eye movement (non‐REM) sleep in patients with newly diagnosed Parkinsons disease (PD) who had never previously received dopaminergic medication. There were no significant differences in the conventional sleep parameters between de novo patients with PD and a healthy control group, but the length of stage 1 sleep and the number of awakenings increased significantly upon administration of dopaminergic drugs. Analyzing the quantitative electroencephalogram (EEG), we observed a significant reduction in the low‐delta frequency range and a nonsignificant increase in the sigma frequency range in de novo patients with PD. The dopaminergic medication also nonsignificantly reduced the low‐delta and sigma frequencies, the latter to the level of the controls. Possible mechanisms that may account for the observed differences are discussed. It is suggested that Parkinsons disease as well as the application of dopaminergic drugs exerts a desynchronizing effect on the sleep EEG that is reflected in a disruption of sleep continuity.

Dehydroepiandrosterone – a neurosteroid

Dehydroepiandrosteone (DHEA) and its sulfate ester (DHEAS) are the major secretory products of the human adrenal glands and serve as precursors for both androgenic and estrogenic steroids. DHEA/S concentrations are particularly high in the brain, and DHEA/S and related steroids can be synthesized de novo in brain glial cells. Therefore, the term ‘neurosteroids’ has been coined for these compounds.

Reduced Efficacy of Growth Hormone-Releasing Hormone in Modulating Sleep Endocrine Activity in the Elderly

In aging, a decline in sleep continuity, a decreased slow wave sleep, an earlier nocturnal cortisol rise, and a blunted growth hormone (GH) secretion occur. Pulsatile administration of GH-releasing hormone (GHRH) in young controls enhanced slow wave sleep and suppressed cortisol release. We administered GHRH 4 x 50 microg or placebo i.v. to 13 healthy seniors (5 women, 8 men, mean age 69.3 y +/- 8.3 SD). We observed significantly reduced nocturnal awakenings and an increased first non-rapid-eye-movement sleep period. In a subgroup (n = 9), we found a significant activation of GH secretion but unchanged cortisol secretion. Our data underscore that GHRH is capable of promoting sleep in the elderly, but much less than in young subjects. Contrasting to young subjects, the hypothalamic-pituitary-adrenocortical system remains unaffected by GHRH in the elderly. These results provide further evidence that a decrease in the efficacy of GHRH is involved in the biological mechanisms underlying aging.

Medial Prefrontal-Hippocampal Connectivity and Motor Memory Consolidation in Depression and Schizophrenia

BACKGROUND Overnight memory consolidation is disturbed in both depression and schizophrenia, creating an ideal situation to investigate the mechanisms underlying sleep-related consolidation and to distinguish disease-specific processes from common elements in their pathophysiology. METHODS We investigated patients with depression and schizophrenia, as well as healthy control subjects (each n = 16), under a motor memory consolidation protocol with functional magnetic resonance imaging and polysomnography. RESULTS In a sequential finger-tapping task associated with the degree of hippocampal-prefrontal cortex functional connectivity during the task, significantly less overnight improvement was identified as a common deficit in both patient groups. A task-related overnight decrease in activation of the basal ganglia was observed in control subjects and schizophrenia patients; in contrast, patients with depression showed an increase. During the task, schizophrenia patients, in comparison with control subjects, additionally recruited adjacent cortical areas, which showed a decrease in functional magnetic resonance imaging activation overnight and were related to disease severity. Effective connectivity analyses revealed that the hippocampus was functionally connected to the motor task network, and the cerebellum decoupled from this network overnight. CONCLUSIONS While both patient groups showed similar deficits in consolidation associated with hippocampal-prefrontal cortex connectivity, other activity patterns more specific for disease pathology differed.

Acute cortisol administration promotes sleep intensity in man

The neuronal mechanisms of sleep generation, in particular synchronization of brain activity in the process of non-rapid-eye movement (non-REM) sleep, has been elucidated in the past decade. A previous study of our group showed that acute administration of cortisol is known to increase slow-wave sleep and suppress rapid-eye movement (REM) sleep in man. To further elucidate the non-REM sleep-promoting effects of cortisol with respect to the synchronization of cortical activity, it is important to establish a sleep-state-specific quantitative EEG analysis. We therefore investigated the effects of repetitive injections of hydrocortisone on spectral composition of sleep EEG in 10 healthy male young volunteers. In addition, we performed high-frequency blood samplings to assess the relation between changes in the sleep EEG and sleep-associated secretion of growth hormone (GH). Cortisol administration resulted in a significant increase in highly synchronized EEG activity including delta and theta frequencies, according to a higher amount of slow-wave sleep. This effect predominated in the first few hours of night sleep. REM sleep was decreased, which appeared to be secondary to the lengthened first sleep cycle. The cortisol-induced stimulation of GH release did not occur in correspondence with the increased slow-wave activity. In view of the sleep impairing properties of corticotropin-releasing hormone (CRH) and the sleep-promoting function of GH-releasing hormone, it appears likely that a negative feedback inhibition of endogenous CRH was the key mechanism mediating the observed results. The cortisol-induced effects on sleep intensity and sleep-associated GH secretion appeared to be driven by different mechanisms.