Introduction Increased rapid eye movement (REM) density, i.e. a high frequency of rapid eye movements in REM-sleep, has been acknowledged as a feature of major depressive disorders [1]. As antidepressants differ in their ability to modify REM-sleep, the aim of this study was to investigate whether REM-density at baseline would be predictive for treatment outcome, and whether REM-sleep suppressive antidepressants would be more effective in patients with high REM-density than other antidepressants.

Context The loss of progesterone during menopause is linked to sleep complaints of the affected women. Previously we demonstrated sleep promoting effects of oral progesterone replacement in postmenopausal women. The oral administration of progesterone, however, is compromised by individual differences in bioavailability and metabolism of the steroid. Objective: We compared the sleep-endocrine effects after intranasal progesterone (MPP22), zolpidem and placebo in healthy postmenopausal women. Design: This was a randomized double-blind cross-over study. Setting: German monocentric study Interventions: Subjects received in randomized order four treatments, 2 doses of intranasal progesterone (4.5 mg and 9 mg of MPP22), 10 mg of zolpidem and placebo. Outcome measures: Main outcome were conventional and quantitative sleep-EEG variables. Secondary outcomes were the subjective sleep variables and the sleep related concentrations of cortisol, growth hormone (GH), melatonin and progesterone. Results: Sleep promoting effects were found after the higher dosage of MPP22 and after zolpidem. Zolpidem prompted benzodiazepine-like effects on quantitative sleep EEG as expected, whereas no such changes were found after the two dosages of MP22. Nocturnal progesterone levels increased after 9.0 mg MPP22. No other changes of hormone secretion were found. Conclusions: Our study shows sleep promoting effects after intranasal progesterone. The spectral signature of intranasal progesterone did not resemble the sleep-EEG alterations induced by GABA active compounds. Progesterone levels were elevated after 9.0 mg MPP22. No other endocrine effects were observed.

A single nucleotide polymorphism substitution from glutamine (Gln, Q) to arginine (Arg, R) at codon 460 of the purinergic P2X7 receptor (P2X7R) has repeatedly been associated with mood disorders. The P2X7R-Gln460Arg variant per se is not compromised in its function. However, heterologous expression of P2X7R-Gln460Arg together with wild-type P2X7R has recently been demonstrated to impair receptor function. Here we show that this also applies to humanized mice coexpressing both human P2X7R variants. Primary hippocampal cells derived from heterozygous mice showed an attenuated calcium uptake upon agonist stimulation. While humanized mice were unaffected in their behavioral repertoire under basal housing conditions, mice that harbor both P2X7R variants showed alterations in their sleep quality resembling signs of a prodromal disease stage. Also healthy heterozygous human subjects showed mild changes in sleep parameters. These results indicate that heterozygosity for the wild-type P2X7R and its mood disorder-associated variant P2X7R-Gln460Arg represents a genetic risk factor, which is potentially able to convey susceptibility to mood disorders.SIGNIFICANCE STATEMENTDepression and bipolar disorder are the most common mood disorders. The P2X7 receptor (P2X7R) regulates many cellular functions. Its polymorphic variant Gln460Arg has repeatedly been associated with mood disorders. Genetically engineered mice, with human P2X7R, revealed that heterozygous mice (i.e., they coexpress the disease-associated Gln460Arg variant together with its normal version) have impaired receptor function and showed sleep disturbances. Human participants with the heterozygote genotype also had subtle alterations in their sleep profile. Our findings suggest that altered P2X7R function in heterozygote individuals disturbs sleep and might increase the risk for developing mood disorders.

Mesenchymal stromal cell (MSC) infusion could be a means to establish tolerance in solid organ recipients. The aim of this prospective, controlled, phase I study was to evaluate the feasibility, safety and tolerability of a single infusion of MSCs in liver transplant recipients.Ten liver transplant recipients under standard immunosuppression received 1.5–3 × 106/kg third-party unrelated MSCs on postoperative day 3 ± 2, and were prospectively compared to a control group of ten liver transplant recipients. As primary endpoints, MSC infusion toxicity was evaluated, and infectious and cancerous complications were prospectively recorded until month 12 in both groups. As secondary endpoints, rejection rate, month-6 graft biopsies, and peripheral blood lymphocyte phenotyping were compared. Progressive immunosuppression weaning was attempted from month 6 to 12 in MSC recipients.No variation in vital parameters or cytokine release syndrome could be detected during and after MSC infusion. No patient developed impairment of organ functions (including liver graft function) following MSC infusion. No increased rate of opportunistic infection or de novo cancer was detected. As secondary endpoints, there was no difference in overall rates of rejection or graft survival. Month-6 biopsies did not demonstrate a difference between groups in the evaluation of rejection according to the Banff criteria, in the fibrosis score or in immunohistochemistry (including Tregs). No difference in peripheral blood lymphocyte typing could be detected. The immunosuppression weaning in MSC recipients was not successful.No side effect of MSC infusion at day 3 after liver transplant could be detected, but this infusion did not promote tolerance. This study opens the way for further MSC or Treg-based trials in liver transplant recipients.Therapy with mesenchymal stromal cells (MSCs) has been proposed as a means to improve results of solid organ transplantation. One of the potential MSC role could be to induce tolerance after liver transplantation, i.e. allowing the cessation of several medications with severe side effects. This study is the first-in-man use of MSC therapy in ten liver transplant recipients. This study did not show toxicity after a single MSC infusion but it was not sufficient to allow withdrawal of immunosuppression.Clinical trial registration number: Eudract: # 2011-001822-81, ClinicalTrials.gov: # NCT 01429038.

Objectives: The relevance of rapid eye movement (REM) sleep in affective disorders originates from its well-known abnormalities in depressed patients, who display disinhibition of REM sleep reflected by increased frequency of rapid eye movements (REM density). In this study we examined whether heart rate variability (HRV) and prefrontal theta cordance, both derived from REM sleep, could represent biomarkers of antidepressant treatment response.Methods: In an open-label, case-control design, thirty-three in-patients (21 females) with a depressive episode were treated with various antidepressants for four weeks. Response to treatment was defined as a >= 50% reduction of HAM-D score at the end of the fourth week. Sleep EEG was recorded after the first and the fourth week of medication. HRV was derived from 3-min artifact-free electrocardiogram segments during REM sleep. Cordance was computed for prefrontal EEG channels in the theta frequency band during tonic REM sleep.Results: HRV during REM sleep was decreased in depressed patients at week four as compared to controls (high effect size; Cohen's d > 1), and showed a negative correlation with REM density in both, healthy subjects and patients at week four. Further, the fourteen responders had significantly higher prefrontal theta cordance as compared to the nineteen non-responders after the first week of antidepressant medication; in contrast, HRV at week one did not discriminate between responders and non responders.Conclusions: Our data suggest that HRV in REM sleep categorizes healthy subjects and depressed patients, whereas REM sleep-derived prefrontal cordance may predict the response to antidepressant treatment in depressed patients. (C) 2017 Elsevier Ltd. All rights reserved.

Corticotropin releasing hormone (CRH) plays key roles in modulation of behavioral and neuroendocrine responses to stress and in sleep regulation. CRH overactivity contributes to the pathophysiology of mood disorders including sleep-EEG changes in patients with depression as reduced slow-wave sleep (SWS) and desinhibition of rapid-eye-movement (REM) sleep. Polymorphisms of the CRH receptor CRH R1 gene appear to be associated with the risk to develop mood disorders. These iclude the single nucleotide polymorphisms (SNP) rs110402 and rs7209436. We investigated associations between these SNPs and sleep EEG in healthy male volunteers.

Introduction. Corticotrophin-releasing hormone (CRH) plays key roles in modulating the behavioral and neuroendocrine responses to stress and in sleep regulation. CRH overactivity participates in the pathophysiology of depression including sleep-EEG changes as REM desinhibtition and reduced slow-wave sleep (SWS). Polymorphisms of the CRH receptor CRHR1 appear to be associated with risk to develop mood disorders. This includes the single nucleotide polymorphisms (SNP) rs110402 and rs7209436. Methods. We investigated associations between these SNPs and sleep EEG in healthy male subjects. Sleep EEG was recorded in 91 young male healthy volunteers. Psychiatric disorders were excluded in their own and family history. Conventional and quantitative sleep-EEG analyses were performed. Results. Homozygous TT and CC and heterozygous CT carriers of both SNPs were compared. The relative time spent in SWS was highest in TT carriers; lower in CT and lowest in CC. Vice versa by trend (n.s.) REM time was lower in TT than in CT and highest in CC EEG power in 1 Hz frequency bin across the whole scalp was strongest in TT, followed by CT and lowest in CC. Discussion. These changes resemble the characteristical sleep-EEG patterns in depressed patients. Our findings are in line with the view that CRH contributes to this pattern.

The trait-like nature of electroencephalogram (EEG) is well established. Furthermore, EEG of wake and non-rapid eye movement (non-REM) sleep has been shown to be highly heritable. However, the genetic effects on REM sleep EEG microstructure are as yet unknown. REM sleep is of special interest since animal and human data suggest a connection between REM sleep abnormalities and the pathophysiology of psychiatric and neurological diseases. Here we report the results of a study in monozygotic (MZ) and dizygotic (DZ) twins examining the heritability of REM sleep EEG. We studied the architecture, spectral composition and phasic parameters of REM sleep and identified genetic effects on whole investigated EEG frequency spectrum as well as phasic REM parameters (REM density, REM activity and organization of REMs in bursts). In addition, cluster analysis based on the morphology of the EEG frequency spectrum revealed that the similarity among MZ twins is close to intra-individual stability. The observed strong genetic effects on REM sleep characteristics establish REM sleep as an important source of endophenotypes for psychiatric and neurological diseases.

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.

Many young females take exogenous hormones as oral contraceptive (OC), a condition rarely controlled for in studies on sleep and memory consolidation even though sex hormones influence consolidation. This study investigated the effects of OCs on sleep-related consolidation of a motor and declarative task, utilizing a daytime nap protocol. Fifteen healthy, young females taking OCs came to the sleep lab for three different conditions: nap with previous learning, wake with previous learning and nap without learning. They underwent each condition twice, once during the ‘pill-active' weeks and once during the ‘pill-free' week, resulting in 6 visits. In all conditions, participants showed a significant off-line consolidation effect, independent of pill week or nap/wake condition. There were no significant differences in sleep stage duration, spindle activity or spectral EEG frequency bands between naps with or without the learning condition. The present data showed a significant off-line enhancement in memory irrespective of potential beneficial effects of a nap. In comparison to previous studies, this may suggest that the use of OCs may enhance off-line memory consolidation in motor and verbal tasks per se. These results stress the importance to control for the use of OCs in studies focusing on memory performance.

The loss of progesterone during menopause is linked to common sleep complaints of the affected women. Consequently, a previous study of our laboratory could demonstrate sleep promoting effects of progesterone replacement in postmenopausal women [1]. The oral of administration of progesterone, however, is compromised by individual differences in bioavailability and metabolism of the steroid. We therefore investigated the sleep EEG effects after intranasal application of progesterone in n = 12 healthy postmenopausal women (50 – 70yrs). Sleep EEG was recorded after 2 doses of intranasal progesterone (MPP 4.5 mg; MPP 9 mg), placebo and after 10 mg of Zolpidem. Each of the 4 conditions consisted of 2 experimental nights (adaptation + examination) with sleep associated hormone assessment (growth hormone, cortisol, melatonin, progesterone, GABA active metabolites). Statistical analysis revealed that both doses of intranasal progesterone increased the duration of stage 2 sleep when compared with placebo. In addition, the higher dose of MPP resulted in an increase of spindle and beta frequencies combined with a decrease of delta oscillations during NREM sleep. Thus, the spectral signature of intranasal progesterone partly resembled the well-known sleep EEG alterations induced by the GABA active compounds. [1] Schuessler et al, Psychoneuroendocrinology 2008; 33: 1124 – 31. This study was supported by M et P Pharma AG, Emmetten, Switzerland.