Changes In REM Sleep Research Articles

Association of Variation in Behavioral Symptoms With Initial Cognitive Phenotype in Adults With Dementia Confirmed by Neuropathology

Behavioral and psychological symptoms of dementia (BPSDs) in association with amnestic and nonamnestic cognitive phenotypes have not been evaluated across diagnoses of Alzheimer disease pathology (ADP), Lewy body-related pathology (LRP), and mixed pathology (ADP-LRP). To determine the clinical phenotypes at the initial visit that are associated with the nature and severity of BPSDs in patients with ADP, LRP, and ADP-LRP. This retrospective longitudinal cohort study included 2422 participants with neuropathologically confirmed ADP, LRP, or mixed ADP-LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019. Participants had a mean (SD) interval of 5.5 (2.8) years from initial visit to autopsy. Clinician-determined diagnosis of change across 10 BPSDs (agitation, apathy, depression, delusions, disinhibition, auditory hallucinations, visual hallucinations, irritability, personality change, and rapid eye movement [REM] sleep behavior) and the highest severity score for behavioral change on the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 2422 participants (1187 with ADP, 904 with ADP-LRP, and 331 with LRP) were included in the analysis (1446 men [59.7%]; mean [SD] age, 74.4 [10.1] years). Compared with initial amnestic symptoms, executive symptoms were associated with a higher risk for 7 of the 10 BPSDs (hazard ratio [HR] range, 1.28-2.45), and visuospatial symptoms were associated with a higher risk for 2 of the 10 BPSDs (HR range, 1.91-2.51), but neither were associated with a low risk for any BPSD. Language symptoms were associated with a low risk of onset for 3 of 10 BPSDs (HR range, 0.43-0.79) and a high risk for 1 BPSD (personality change) (HR, 1.42 [95% CI, 1.10-1.83]). Participants with LRP had a lower risk for agitation (HR, 0.74 [95% CI, 0.60-0.92]), disinhibition (HR, 0.78 [95% CI, 0.62-0.99]), and irritability (HR, 0.81 [95% CI, 0.68-0.96]) and a higher risk for apathy (HR, 1.19 [95% CI, 1.02-1.38]), depression (HR, 1.32 [95% CI, 1.12-1.55]), auditory (HR, 2.00 [95% CI, 1.37-2.93]) and visual (HR, 2.78 [95% CI, 2.21-3.49]) hallucinations, and REM sleep behavior changes (HR, 4.77 [95% CI, 3.61-6.31]) compared with the ADP group. The ADP-LRP group had a higher risk for delusions (HR, 1.27 [95% CI, 1.08-1.48]), auditory (HR, 1.62 [95% CI, 1.21-2.15]) and visual (HR, 1.57 [95% CI, 1.30-1.89]) hallucinations, and REM sleep behavior changes (HR, 2.10 [95% CI, 1.63-2.70]) than the ADP group and a lower risk for visual hallucinations (HR, 0.56 [95% CI, 0.45-0.71]) and REM sleep behavior changes (HR, 0.44 [95% CI, 0.34-0.57) than the LRP group. Overall, women showed a lower risk of agitation (HR, 0.86 [95% CI, 0.75-0.98]), apathy (HR, 0.79 [95% CI, 0.71-0.87]), visual hallucinations (HR, 0.76 [95% CI, 0.64-0.90]), irritability (HR, 0.77 [95% CI, 0.69-0.86]), and REM sleep behavior change (HR, 0.45 [95% CI, 0.35-0.58]) and a higher risk of depression (HR, 1.26 [95% CI, 1.13-1.41]). Older age was associated with a lower risk of most BPSDs (HR range, 0.98-0.99) except delusions (HR, 1.00 [95% CI, 1.00-1.01]) and auditory hallucinations (HR, 0.99 [95% CI, 0.97-1.00]) and a low NPI-Q composite score (β = -0.07 [95% CI, -0.08 to -0.05]; P < .001). These findings suggest that the risks of BPSDs differ with respect to the initial cognitive phenotype, underlying neuropathology, age, and sex. Awareness of these associations could be helpful in dementia management.

Objective underpinnings of self-reported sleep quality in middle-aged and older adults: The importance of N2 and wakefulness

Study objectivesThe measurable aspects of brain function (polysomnography, PSG) that are correlated with sleep satisfaction are poorly understood. Using recent developments in automated sleep scoring, which remove the within- and between-rater error associated with human scoring, we examine whether PSG measures are associated with sleep satisfaction. Design and settingA single night of PSG data was compared to contemporaneously collected measures of sleep satisfaction with Random Forest regressions. Whole and partial night PSG data were scored using a novel machine learning algorithm. ParticipantsCommunity-dwelling adults (N = 3165) who participated in the Sleep Heart Health Study. InterventionsNone. Measurements and resultsModels explained 30% of sleep depth and 27% of sleep restfulness, with a similar top four predictors: minutes of N2 sleep, sleep efficiency, age, and minutes of wake after sleep onset (WASO). With increasing self-reported sleep quality, there was a progressive increase in N2 and decrease in WASO of similar magnitude, without systematic changes in N1, N3 or REM sleep. In comparing those with the best and worst self-reported sleep satisfaction, there was a range of approximately 30 min more N2, 30 min less WASO, an improvement of sleep efficiency of 7–8%, and an age span of 3–5 years. Examination of sleep most proximal to morning awakening revealed no greater explanatory power than the whole-night data set. ConclusionsHigher N2 and concomitant lower wake is associated with improved sleep satisfaction. Interventions that specifically target these may be suitable for improving the self-reported sleep experience.

REM sleep latency changes after version 2.1 of the AASM manual for scoring sleep

BackgroundThe classical criteria for scoring REM sleep changed in version 2.1 of the AASM manual for scoring sleep, by allowing N1 epochs with atonia precedent and contiguous to definite REM sleep to be scored as REM sleep in the absence of rapid eye movements when the EEG was compatible. This may shorten the REM latency in the Multiple Sleep Latency Test (MSLT) in naps with wake/N1 to REM transitions, characteristic of narcolepsy type 1. Since REM latency of <5 or <6 min is a biomarker of NT-1 we have assessed the impact of this change in scoring REM sleep in the MSLT. MethodsNinety-two consecutive five-nap MSLT studies (460 naps) performed in our center between 2013 and 2019 for evaluation of hypersomnolence with ≥1 sleep onset REM (SOREM) naps were included. REM latencies were measured using both classical and new criteria. ResultsSOREMs occurred in 255 (55.9%) naps, 134 directly from wake/N1. By using the new criteria REM latency shortened in 29.1% of these naps (mean 0.2 ± 0.5, range 0–3 min, p < 0.01), predominantly in females. Twenty-eight percent of MSLTs had at least one nap with a shortened REM latency (mean 0.1 min ± 0.2, p < 0.01). Only two MSLTs changed their REM latency to <5 min and none to <6 min with the new rules. ConclusionsThe criterion to define REM sleep onset significantly influences its latency and should be considered when comparing studies performed before or after version 2.1 modification. The clinical relevance of this scoring change is probably minimal.

Insomnia in Patients with Borderline Personality Disorder.

ObjectiveBoth sleep disorders and BPD are prevalent in the population, and one is often a comorbidity of the other. This narrative review aims to assess contemporary literature and scientific databases to provide the current state of knowledge about sleep disorders in patients with borderline personality disorder (BPD) and clinical suggestions for managing sleep disorders in BPD patients and future research direction.MethodsArticles were acquired via PubMed and Web of Science, and papers published between January 1980 and October 2020 were extracted. Authors made a series of literature searches using the keywords: Sleep problems, Insomnia, Nightmares, Obstructive sleep apnea, Borderline personality disorder. The inclusion criteria were: published in peer-reviewed journals; studies in humans; or reviews on the related topic; English language. The exclusion criteria were: abstracts from conferences; commentaries; subjects younger than 18 years. After an inspection of the full texts, 42 papers from 101 were selected. Secondary documents from the reference lists of the primary designated papers were searched, assessed for suitability, and included. In total, 71 papers were included in the review process.ResultsSleep disturbance is common among patients with BPD. Nevertheless, the number of investigations is limited, and the prevalence differs between 5–45%. Studies assessing objective changes in sleep architecture in BPD show inconsistent results. Some of them identify REM sleep changes and a decrease in slow-wave sleep, while other studies found no objective sleep architecture changes. There is also a higher prevalence of nightmares in patients with BPD. Untreated insomnia can worsen BPD symptoms via interference with emotional regulation. BPD itself seems to influence the subjective quality of sleep significantly. Proper diagnosis and treatment of sleep disorders in patients with BPD could lead to better results in therapy. Psychotherapeutic approaches can improve both sleep disorders and BPD symptoms.ConclusionRecognising and managing sleep disorders in patients with BPD may help alleviate the disorder’s symptoms. Treatment of people with BPD may be more effective if the treatment plan explicitly addresses sleep problems. Further research is needed to reach reliable conclusions.

Multimodal neuroimaging correlates of NREM and REM sleep: EEG spectral power in aging

AbstractBackgroundSleep disturbances have been associated with cognitive decline and Alzheimer’s disease (AD), with growing efforts to understand how these changes may relate to AD pathophysiology. However, we lack a comprehensive overview of the associations between objectively‐measured sleep oscillations and brain changes in aging so that efficient treatment strategies could be developed. Using an unbiased, fast, and powerful quantitative (spectral) analysis of sleep EEG rhythms, we assessed the relationships between both non‐rapid eye movement (NREM) and REM sleep oscillations, and amyloid burden, gray matter (GM) volume and perfusion in cognitively unimpaired older adults (CUOA).Method125 CUOA from the Age‐Well randomized controlled trial underwent a neuropsychological assessment, an ambulatory polysomnography recording and a structural MRI. A Florbetapir‐PET scan was also performed with early and late acquisitions to measure brain perfusion and amyloid burden respectively. Normalized EEG spectral power values were obtained using the ASEEGA® algorithm for delta (0.1‐4 Hz), theta (4‐8 Hz), alpha (8‐12 Hz) and beta (16‐50 Hz) EEG frequency bands, over the Cz‐Pz derivation (Berthomier et al., 2007). Voxel‐wise multiple regressions were then conducted between EEG spectral power values and neuroimaging data (i.e., GM volume, perfusion and amyloid burden), separately for NREM and REM sleep, controlling for age, gender, education, the apnea‐hypopnea index, sleep medication use, and the ApoE4 status.ResultLower NREM sleep delta power, reflecting a decrease in slow wave activity, was related to decreased GM volume and perfusion in fronto‐cingulate areas, but not to amyloid deposition. By contrast, decreased REM sleep theta power was associated with i) greater amyloid deposition in frontal, cingulate, parietal and temporal areas; ii) lower GM volume in frontal, temporal, occipital and insular cortices, and iii) increased perfusion in frontal and parietal regions.ConclusionBoth NREM and REM sleep alterations were associated with structural and functional changes in regions sensitive to aging and AD pathophysiology. Importantly, REM sleep changes were associated with greater amyloid deposition. This may be due to early changes in cholinergic structures, acetylcholine playing a neuroprotective role against amyloid. Thus older individuals with REM sleep alterations may be more at risk of belonging to the Alzheimer’s continuum.

Sleep in Isolated, Confined, and Extreme (ICE): A Review on the Different Factors Affecting Human Sleep in ICE.

The recently renewed focus on the human exploration of outer space has boosted the interest toward a variety of questions regarding health of astronauts and cosmonauts. Among the others, sleep has traditionally been considered a central issue. To extend the research chances, human sleep alterations have been investigated in several analog environments, called ICEs (Isolated, Confined, and Extreme). ICEs share different features with the spaceflight itself and have been implemented in natural facilities and artificial simulations. The current paper presents a systematic review of research findings on sleep disturbances in ICEs. We looked for evidence from studies run in polar settings (mostly Antarctica) during space missions, Head-Down Bed-Rest protocols, simulations, and in a few ICE-resembling settings such as caves and submarines. Even though research has shown that sleep can be widely affected in ICEs, mostly evidencing general and non-specific changes in REM and SWS sleep, results show a very blurred picture, often with contradictory findings. The variable coexistence of the many factors characterizing the ICE environments (such as isolation and confinement, microgravity, circadian disentrainment, hypoxia, noise levels, and radiations) does not provide a clear indication of what role is played by each factor per se or in association one with each other in determining the pattern observed, and how. Most importantly, a number of methodological limitations contribute immensely to the unclear pattern of results reported in the literature. Among them, small sample sizes, small effect sizes, and large variability among experimental conditions, protocols, and measurements make it difficult to draw hints about whether sleep alterations in ICEs do exist due to the specific environmental characteristics, and which of them plays a major role. More systematic and cross-settings research is needed to address the mechanisms underlying the sleep alterations in ICE environments and possibly develop appropriate countermeasures to be used during long-term space missions.

0354 Age-Related Spectral Changes in NREM And REM Sleep in Mice are Global and Not Local

Abstract Introduction Brain topography modulates age-related changes in the human sleep electroencephalogram, which are linked with differences in integrity of specific cortical areas and may reflect local changes in sleep homeostasis. In mice, there is conflicting evidence regarding the topography of age-related changes for NREM and REM sleep. To disambiguate this issue, we investigated in mice the topography of age-related spectral differences for REM and NREM sleep. Methods LFP electrodes were implanted in 5 cortical areas and in the hippocampus of 17 C57/BL6 mice (8 young and 9 old, mean age = 7.5 and 16 months). Mice LFPs were recorded for a week and states of vigilance were semi-automatically detected in light and dark periods (12h-12h). Spectral analysis was run on 4s windows. Values were averaged for each electrode and in each period of the light/dark cycle in REM/NREM sleep for slow delta (0.25-2Hz), delta (2-4Hz), theta (4-8Hz), sigma (10-16Hz) and ripples (150-200Hz). Mixed models were computed separately for REM and NREM in dark and light period, with age as group factor and electrode and frequency as repeated factors. Results Two-way interactions were found between age and frequency and between electrode and frequency, for NREM and REM in dark and light periods. Each frequency band, except ripples, showed a topographical signature in NREM and REM (e.g. higher power in anterior compared to posterior areas for delta band in NREM sleep). These relative patterns did not change in older mice, but global changes occurred on all electrodes: in older mice, delta power was globally higher in NREM and REM sleep whereas sigma power was lower in REM sleep. Conclusion Age-related changes in spectral power of sleeping mice do not vary according to brain topography as in humans. Sleep deprivation studies are needed to investigate whether age is associated with global changes in sleep homeostasis in mice. Support This work has been supported by the Quebec Fonds de Recherche Nature et Technologies (FQRNT).

Dynamic REM Sleep Modulation by Ambient Temperature and the Critical Role of the Melanin-Concentrating Hormone System

Ambient temperature (Ta) warming toward the high end of the thermoneutral zone (TNZ) preferentially increasesrapid eye movement (REM) sleep over non-REM (NREM) sleep across species. The control and function of this temperature-induced REM sleepexpression have remained unknown. Melanin-concentrating hormone (MCH) neurons play an important role in REM sleep control. We hypothesize that the MCH system may modulate REM sleep as a function of Ta. Here, we show that wild-type (WT) mice dynamically increased REM sleep durations specifically during warm Ta pulsing within the TNZ, compared to both the TNZ cool and baseline constant Ta conditions, without significantly affecting either wake or NREM sleep durations. However, genetically engineered MCH receptor-1 knockout (MCHR1-KO) mice showed no significant changes in REM sleep as a function of Ta, even with increased sleep pressure following a 4-h sleep deprivation. Using MCH-cre mice transduced with channelrhodopsin, we then optogenetically activated MCH neurons time locked with Ta warming, showing an increase in REM sleep expression beyond what Ta warming in yellow fluorescent protein (YFP) control mice achieved. Finally, in mice transduced with archaerhodopsin-T, semi-chronic optogenetic MCH neuronal silencing during Ta warming completely blocked the increase in REM sleep seen in YFP controls. These data demonstrate a previously unknown role for the MCH system in the dynamic output expression of REM sleep during Ta manipulation. These findings are consistent with the energy allocation hypothesis of sleep function, suggesting that endotherms have evolved neural circuits to opportunistically express REM sleep when the need for thermoregulatory defense is minimized.

Associations Between Sleep Quality, Sleep Architecture and Sleep Disordered Breathing and Memory After Continuous Positive Airway Pressure in Patients with Obstructive Sleep Apnea in the Apnea Positive Pressure Long-term Efficacy Study (APPLES).

ObjectiveThe role of sleep architecture in consolidation of memory has not been extensively investigated. In this study, the association of continuous positive airway pressure (CPAP) and sleep architecture and quality, and sleep disordered breathing on changes in memory are explored during the course of a 6 month clinical trial of CPAP or sham CPAP (APPLES).Methods848 participants had polysomnographic and memory assessments (Buschke Selective Reminding Test [Buschke] and Digit Symbol Substitution Test [DSST]) at baseline, CPAP/Sham CPAP titration, and the 2 and 6 month time points. Half were assigned to the CPAP and Sham CPAP groups respectively. Changes in performance on the Buschke and the DSST were analyzed over the course of the study between CPAP and Sham CPAP as well as in relationship to changes in sleep architecture, sleep quality and sleep disordered breathing (SDB).ResultsSleep architecture, sleep quality and SDB improved in the CPAP group at 6 months; performance on the Buschke and DSST improved equally in both CPAP and Sham CPAP groups. There also were no significant correlations between changes in the amount or percentage of sleep stages between baseline and the 6 months, and corresponding changes in either the Buschke or the DSST. However, when stratified by the upper quartile and lower 3 quartiles, greater changes in the Buschke occurred over 6 months in the top quartile of total sleep time (5.7±7.3 vs. 4.0±6.8, p≤0.01) and amount of N3 sleep (55.9±7.7 vs. 53.6±8.9 min, p≤0.01). Those with more %N3 at 6 months scored better on the Buschke as well (55.9±7.8 vs. 53.6±8.9, p≤0.01). Borderline improvement in the DSST over 6 months was observed in the top quartiles of amount of N3 and %N3. Those in the top quartile of the amount of REM and %REM also showed greater improvement in the Buschke after 6 months. No differences were observed for the AHI, but those in the top quartile of oxygen desaturation had worse scores on the Buschke at 6 months. CPAP/Sham CPAP adherence did not impact 6 month Buschke or DSST performance.ConclusionsCPAP improved long-term sleep duration, quality and architecture, but did not memory. However, large changes in REM and N3 sleep as well as moderate amounts of nocturnal hypoxemia are associated with changes in assessments of memory.

0064 Lateral Hypothalamic Control of REM Sleep Expression During Ambient Temperature Warming

Sleep and thermoregulation are tightly integrated. Moreover, ambient temperature (Ta) warming preferentially increases REM sleep over NREM sleep across species. Although the role of the anterior hypothalamus in thermoregulation and NREM sleep expression are well documented, the hypothalamic control of REM sleep during ambient temperature manipulation remains to be determined. We examined the role of the posterior lateral hypothalamus (LH) melanin concentrating hormone (MCH) system in the modulation of REM sleep during Ta manipulation. Genetically engineered MCH-R1-knockout (KO) mice or MCH::cre mice implanted with cortical EEG and neck EMG electrodes were used for these experiments. Mice were housed at 23.0 ± 1.0°C in their home cages in a temperature-controlled cabinet. During the light period at two hour intervals, four bouts of rapid Ta warming to a maximum of 31.7°C were achieved for 30 minutes with a thermostatically controlled combination of convection heater and indirect infrared lamp. To optogenetically stimulate MCH neurons, we stereotactically injected AAV2-ChR2-eYFP or AAV2-eYFP (controls) in the LH of MCH::Cre mice. In wild type (WT) controls, REM sleep was significantly increased in the warm (27.5–31°C) versus cool (24.0–27.5˚C) condition. However, MCH-R1-KO mice showed no significant changes in REM sleep as a function of Ta. Random semi-chronic optical activation of MCH neurons significantly increased NREM-to-REM sleep transitions, and prolonged REM sleep durations compared to YFP controls, but did not affect NREM sleep. Additional Ta warming had an additive effect on increasing REM sleep, demonstrating that optical stimulation of MCH neurons in combination with Ta warming was able to “over-drive” the expression of REM sleep beyond what optical stimulation or Ta warming alone could achieve. Indeed, optical stimulation had the same effect on increasing REM sleep expression as Ta warming in the YFP control mice. These data support a key role for the MCH system in the output expression of REM sleep during Ta manipulation, and show that concomitant MCH activation with Ta warming can over-express this effect. Ohio Sleep Medicine and Neuroscience Institute, Inselspital Bern University Hospital.

0272 Thinning of Medial Frontal and Anterior Cingulate Cortices Explain Age-related Changes in REM and NREM Sleep

0272 Thinning of Medial Frontal and Anterior Cingulate Cortices Explain Age-related Changes in REM and NREM Sleep

Editors' note: Sleep architecture and the risk of incident dementia in the community

In “Sleep architecture and the risk of incident dementia in the community,” the authors found an association between dementia risk and lower percentage of REM sleep. They hypothesized that changes in REM sleep may be protective against cognitive decline. To further evaluate this theory, Dr. Kim suggests a longitudinal prospective cohort study of patients exposed to medications that reduce REM sleep to determine whether they have an increased risk of dementia. Authors Pase et al. agree as long as confounding factors can be controlled. In “Sleep architecture and the risk of incident dementia in the community,” the authors found an association between dementia risk and lower percentage of REM sleep. They hypothesized that changes in REM sleep may be protective against cognitive decline.

Editors' note: The state of academic neurology departments in the United States, 2016: A national survey

In the special editorial “The state of academic neurology departments in the United States, 2016: A national survey,” author Gooch highlighted how most neurology faculty members are not on a tenure track and that almost 40% of academic neurology departments have purely clinical faculty with no educational or research responsibilities. Dr. Meador adds data from other surveys indicating that time spent by academic neurologists on research and education has sharply declined over the last 30 years and questions whether this new balance is appropriate. Author Gooch responds that cuts to research funding and clinical reimbursement will likely make the situation worse and that academic leaders and faculty should engage at the institutional and national levels in order to have input into what the future of academic neurology looks like. In “Sleep architecture and the risk of incident dementia in the community,” the authors found an association between dementia risk and lower percentage of REM sleep. They hypothesized that changes in REM sleep may be protective against cognitive decline.

Reader response: Sleep architecture and the risk of incident dementia in the community.

Pase et al.1 stated changes in REM sleep may not be a marker of prodromal dementia, but may actually be protective against cognitive decline, and further studies were needed. The authors used a model to account for confounding factors including antidepressant use, which is known to suppress REM sleep in healthy and depressed patients.2 If REM sleep is protective for dementia, it would be interesting to perform a longitudinal prospective cohort study with polysomnogram data to analyze if exposure to medications that reduce REM sleep has an increased incidence of dementia. This may be confounded by psychiatric factors, such as heightened anxiety being implicated as a possible risk factor for dementia.3 However, medications, such as duloxetine, are often used for nonpsychiatric indications (e.g., neurogenic pain).

0654 PSG AND MSLT CHARACTERIZATION OF REM SLEEP WITHOUT ATONIA AND REM BEHAVIOR DISORDER AMONG PEDIATRIC PATIENTS WITH NARCOLEPSY

In this study, we aim to determine the prevalence of nocturnal RWA and RBD in a drug-naïve pediatric narcolepsy population and compare findings to pediatric patients with other central nervous system hypersomnias and controls. We additionally aim to determine the prevalence of RWA and RBD during daytime REM bouts captured during MSLT testing. Given that RSWA, RBD and cataplexy are thought to underlie dysfunction within REM on/off neurons, we hypothesize that RSWA and RBD will be found only during the daytime and nighttime REM periods among patients with narcolepsy type 1. Based on sleep study results and clinical history, we grouped subjects as narcolepsy type 1 (N1, n=11), narcolepsy type 2 (N2, n=4), idiopathic hypersomnia (IH, n=5) and controls (C, n=11). Mean age of patients was 13 years and 49% were female. RSWA and RBD were scored based on American Academy of Sleep Medicine specifications. We calculated a RSWA index for each subject (number of REM epochs with RSWA/total REM epochs). On the PSG, we only detected RBD among N1 patients (2/11, 18%) but found no difference in the frequency of RSWA among groups (P=0.18). Notably, all N1 patients had RSWA and the RSWA index was 5.5x higher on their nocturnal PSGs compared to all other groups (P=0.002). On MSLT, 82% of N1 patients had RSWA and RSWA was not detected in any other groups. The two N1 patients with RBD during the PSG also had RBD on the MSLT. RSWA is uniquely detected among N1 patients on the MSLT but not the PSG. However, the frequency of nocturnal RSWA is markedly higher in N1 pediatric patients compared to other groups, findings consistent with adult narcolepsy data. Our findings have practical implications about scoring pediatric MSLTs as epochs of REM may lack the classic atonia in N1. Furthermore, the frequent presence of RSWA across day and night REM periods and higher mean RSWA index in the N1 group suggest that greater hypocretin loss results in phenotypic changes in REM sleep in addition to dysregulated REM sleep bouts. None.

Altered sleep patterns in patients with non-functional GHRH receptor.

GH-releasing hormone (GHRH) exerts hypnotic actions increasing the non-rapid eye movement (NREM) sleep. Conversely, GH stimulates the REM sleep. GH deficiency (GHD) often leads to sleep problems, daytime fatigue and reduced quality of life (QoL). GHD may be due to lack of hypothalamic GHRH or destruction of somatotroph cells. We have described a cohort with isolated GHD (IGHD) due to GHRH resistance caused by a homozygous null mutation (c.57 + 1G > A) in the GHRH receptor gene. They have normal QoL and no obvious complaints of chronic tiredness. The aim of this study was to determine the sleep quality in these subjects. A cross-sectional study was carried out in 21 adult IGHD subjects, and 21 age- and gender-matched controls. Objective sleep assessment included polygraphic records of the awake, stages NREM [N1 (drowsiness), N2 and N3 (already sleeping)] and REM (R). Subjective evaluation included the Pittsburgh Sleep Quality Index, the Insomnia Severity Index and the Epworth Sleepiness Scale. IGHD subjects showed a reduction in sleep efficiency (P = 0.007), total sleep time (P = 0.028), duration of N2 and R in minutes (P = 0.026 and P = 0.046 respectively), but had increased duration and percentage of N1 stage (P = 0.029 and P = 0.022 respectively), wake (P = 0.007) and wake-time after sleep onset (P = 0.017). There was no difference in N3 or in sleep quality questionnaire scores. Patients with IGHD due to GHRH resistance exhibit objective reduction in the sleep quality, with changes in NREM and REM sleep, with no detectable subjective consequences. GHRH resistance seems to have a preponderant role over GHD in the sleep quality of these subjects.

RNA‐Seq Analysis Reveals Ectopic Expression of Truncated Non‐Functional Serotonin Transporter in the Hippocampus of SERT‐KO Mice

The serotonergic system innervates the cortex, entorhinal cortex, hippocampus (HPC), nucleus accumbens, amygdala and anterior hypothalamus via serotonergic neurons arising from raphe nuclei in the mid and hindbrain. These structures are part of the limbic system, which is involved in emotions and motivation. Termini of the serotonergic neurons that innervate these limbic regions contain the serotonin transporter (SERT), which is a therapeutic target for many mood disorders. To date, insight into the link between SERT and its impact on these psychiatric conditions has been afforded by the use of a SERT‐deficient mouse line (SERT‐KO). Numerous studies have used this murine model to investigate serotonergic function in the HPC and links to neuropsychiatric disorders. In the present study, RNA‐Seq was performed on isolated HPC from 9 week old male C57BL6/J (WT) and B6.129(Cg)‐Slc6a4tm1Kpl/J (SERT‐KO) mice yielding 28–34 million mappable reads, indicating exceptional sequencing depth of the mouse genome. Reads were aligned to the mouse genome (mm10) using Tophat v2.0.13 and fragments were assigned to genes using Feature Counts v1.4.6. Differential gene expression analysis was performed with R/Bioconductor package DESeq2 v1.10.1 and analyzed with Ingenuity Pathway Analysis (IPA, Qiagen). Unexpectedly, an mRNA species capable of coding for amino acids 115 to 630 of SERT was detected in KO HPC at levels significantly higher than full‐length SERT in WT HPC samples (219 vs. 2 fragment counts, respectively). The truncated SERT transcript parallels the genetic mutation used to create the SERT‐KO mouse where exon 2 of the promoter region was replaced with a PGK neomycin‐polyA cassette. The altered 5′‐UTR region in the SERT‐KO mice appears to allow for ectopic expression of truncated SERT mRNA in the cell bodies of pyramidal, granule and/or glial cells residing in the HPC. Expression of SERT mRNA in the HPC of WT and KO mice was normalized to the reference gene Beta‐2‐microglobulin (B2M), revealing a 155‐fold increase in SERT mRNA in the KO mouse vs WT. IPA analysis of genes showing significant expression changes identified a number of genes involved in the “Unfolded Protein Response (UPR)” and “Endoplasmic Reticulum Stress” pathways consistent with ectopic expression of the truncated SERT mRNA which does not code for transmembrane domain 1 of SERT and likely result in mis‐ or unfolded protein. In addition, IPA identified the “Circadian Rhythm Signaling” pathway in line with previous reports looking at changes in circadian rhythm and REM sleep in SERT‐KO mice. IPA “upstream” analysis also suggests that expression changes of several genes were linked to brain‐derived neurotrophic factor (BDNF) and whereas BDNF expression changes were detected between WT and SERT‐KO samples, the difference did not reach significance. However, this analysis does not discriminate isoforms of BDNF, an area of future focus. Finally, although our study focuses on the HPC, other tissues including those outside the central nervous system could be affected by inappropriate SERT expression.Support or Funding InformationNIH‐NIGMS P20 GM104360

Sleep electroencephalography as a biomarker in depression

Sleep electroencephalography as a biomarker in depression Axel Steiger, Marcel Pawlowski, Mayumi Kimura Max Planck Institute of Psychiatry, Munich, Germany Abstract: The sleep electroencephalogram (EEG) provides biomarkers of depression, which may help with diagnosis, prediction of therapy response, and prognosis in the treatment of depression. In patients with depression, characteristic sleep EEG changes include impaired sleep continuity, disinhibition of rapid-eye-movement (REM) sleep, and impaired non-REM sleep. Most antidepressants suppress REM sleep in depressed patients, healthy volunteers, and in animal models. REM suppression appears to be an important, but not an absolute requirement, for antidepressive effects of a substance. Enhanced REM density, a measure for frequency of REM, characterizes high-risk probands for affective disorders. REM-sleep changes were also found in animal models of depression. Sleep-EEG variables were shown to predict the response to treatment with antidepressants. Furthermore, certain clusters of sleep EEG variables predicted the course of the disorder for several years. Some of the predicted sleep EEG markers appear to be related to hypothalamic&ndash;pituitary&ndash;adrenal system activity. Keywords: biomarkers, depression, sleep EEG, antidepressants, prediction, animal models

Overnight improvements in two REM sleep-sensitive tasks are associated with both REM and NREM sleep changes, sleep spindle features, and awakenings for dream recall

Memory consolidation is associated with sleep physiology but the contribution of specific sleep stages remains controversial. To clarify the contribution of REM sleep, participants were administered two REM sleep-sensitive tasks to determine if associated changes occurred only in REM sleep. Twenty-two participants (7 men) were administered the Corsi Block Tapping and Tower of Hanoi tasks prior to and again after a night of sleep. Task improvers and non-improvers were compared for sleep structure, sleep spindles, and dream recall. Control participants (N=15) completed the tasks twice during the day without intervening sleep. Overnight Corsi Block improvement was associated with more REM sleep whereas Tower of Hanoi improvement was associated with more N2 sleep. Corsi Block improvement correlated positively with %REM sleep and Tower of Hanoi improvement with %N2 sleep. Post-hoc analyses suggest Tower of Hanoi effects—but not Corsi Block effects—are due to trait differences. Sleep spindle density was associated with Tower of Hanoi improvement whereas spindle amplitude correlated with Corsi Block improvement. Number of REM awakenings for dream reporting (but not dream recall per se) was associated with Corsi Block, but not Tower of Hanoi, improvement but was confounded with REM sleep time. This non-replication of one of 2 REM-sensitive task effects challenges both ‘dual-process’ and ‘sequential’ or ‘sleep organization’ models of sleep-dependent learning and points rather to capacity limitations on REM sleep. Experimental awakenings for sampling dream mentation may not perturb sleep-dependent learning effects; they may even enhance them.

Fear conditioning, safety learning, and sleep in humans.

Fear conditioning is considered an animal model of post-traumatic stress disorder. Such models have shown fear conditioning disrupts subsequent rapid eye movement sleep (REM). Here, we provide a translation of these models into humans. Using the fear potentiated startle (FPS) procedure, we examined the effects of fear conditioning and safety signal learning on subsequent REM sleep in healthy adults. We also examined the effects of changes in REM sleep on retention of fear and safety learning. Participants (n = 42 normal controls) spent 3 consecutive nights in the laboratory. The first was an adaptation night. Following the second night, we administered a FPS procedure that included pairing a wrist shock with a threat signal and a safety signal never paired with a shock. The next day, we administered the FPS procedure again, with no wrist shocks to any stimulus, to measure retention of fear and safety. Canonical correlations assessed the relationship between FPS response and REM sleep. Results demonstrated that increased safety signal learning during the initial acquisition phase was associated with increased REM sleep consolidation that night, with 28.4% of the variance in increased REM sleep consolidation from baseline accounted for by safety signal learning. Overnight REM sleep was, in turn, related to overnight retention of fear and safety learning, with 22.5% of the variance in startle retention accounted for by REM sleep. These data suggest that sleep difficulties, specifically REM sleep fragmentation, may play a mechanistic role in post-traumatic stress disorder via an influence on safety signal learning and/or threat-safety discrimination.