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Study Objectives Fast frequency sleep spindles are reduced in aging and Alzheimer’s disease (AD), but the mechanisms and functional relevance of these deficits remain unclear. The study objective was to identify AD biomarkers associated with fast sleep spindle deficits in cognitively unimpaired older adults at risk for AD. Methods Fifty-eight cognitively unimpaired, β-amyloid-negative, older adults (mean ± SD; 61.4 ± 6.3 years, 38 female) enriched with parental history of AD (77.6%) and apolipoprotein E (APOE) ε4 positivity (25.9%) completed the study. Cerebrospinal fluid (CSF) biomarkers of central nervous system inflammation, β-amyloid and tau proteins, and neurodegeneration were combined with polysomnography (PSG) using high-density electroencephalography and assessment of overnight memory retention. Parallelized serial mediation models were used to assess indirect effects of age on fast frequency (13 to Results Glial activation was associated with prefrontal fast frequency sleep spindle expression deficits. While adjusting for sex, APOE ε4 genotype, apnea–hypopnea index, and time between CSF sampling and sleep study, serial mediation models detected indirect effects of age on fast sleep spindle expression through microglial activation markers and then tau phosphorylation and synaptic degeneration markers. Sleep spindle expression at these electrodes was also associated with overnight memory retention in multiple regression models adjusting for covariates. Conclusions These findings point toward microglia dysfunction as associated with tau phosphorylation, synaptic loss, sleep spindle deficits, and memory impairment even prior to β-amyloid positivity, thus offering a promising candidate therapeutic target to arrest cognitive decline associated with aging and AD.

Sleep oscillations provide a key substrate to facilitate memory processing, the underlying mechanism of which may involve the overnight homeostatic regulation of plasticity at a synaptic and whole-network level. However, there remains a lack of human data demonstrating if and how sleep enhances memory consolidation and associated neural homeostasis. We combined intracranial recordings and scalp electroencephalography (EEG) in humans to reveal a new role for rapid eye movement (REM) sleep in promoting the homeostatic recalibration of optimal excitation/inhibition-balance. Moreover, the extent of this REM-sleep homeostatic recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal— neocortical excitability favoring remembering rather than forgetting. The findings describe a novel, fundamental role of human REM sleep in maintaining neural homeostasis, thereby enhancing long-term memory.

Study Objectives To determine whether subjective measures of exercise and sleep are associated with cognitive complaints and whether exercise effects are mediated by sleep. Methods This study analyzed questionnaire data from adults (18–89) enrolled in a recruitment registry. The Cognitive Function Instrument (CFI) assessed cognitive complaints. Medical Outcomes Study Sleep Scale (MOS-SS) subscales and factor scores assessed sleep quality, daytime sleepiness, nighttime disturbance, and insomnia and obstructive sleep apnea (OSA)-like symptoms. Exercise frequency was defined as the weekly number of exercise sessions. Exercise frequency, MOS-SS subscales, and factor scores were examined as predictors of CFI score, adjusting for age, body mass index, education, sex, cancer diagnosis, antidepressant usage, psychiatric conditions, and medical comorbidities. Analyses of covariance examined the relationship between sleep duration groups (short, mid-range, and long) and CFI score, adjusting for covariates. Mediation by sleep in the exercise-CFI score relationship was tested. Results Data from 2106 adults were analyzed. Exercise and MOS-SS subscales and factor scores were associated with CFI score. Higher Sleep Adequacy scores were associated with fewer cognitive complaints, whereas higher Sleep Somnolence, Sleep Disturbance, Sleep Problems Index I, Sleep Problems Index II, and factor scores were associated with more cognitive complaints. MOS-SS subscales and factor scores, except Sleep Disturbance and the insomnia factor score, mediated the association between exercise and cognitive complaints. Conclusions The relationship between exercise frequency and subjective cognitive performance is mediated by sleep. In particular, the mediation effect appears to be driven by symptoms possibly suggestive of OSA which are negatively associated with exercise engagement, sleep quality, daytime sleepiness, and subjective cognitive performance.

Recent meta-analyses suggest that insomnia specifically confers risk for Alzheimer’s Disease (AD); however, the precise mechanisms by which this occurs are not well understood. In this review, we discuss candidate mechanisms linking insomnia features to AD neuropathophysiology, potentially driving increased AD risk in insomnia patients. First, we discuss epidemiological evidence tying insomnia to AD and summarize the behavioral and neurobiological features of insomnia, as well as AD pathologies. We propose that facets of hyperarousal, a central etiological feature of insomnia, act upon underlying mechanisms contributing to AD pathogenesis. Additionally, we outline how objective short sleep duration and circadian dysregulation, other key aspects of insomnia, may act as compounding pathways to exacerbate disease expression. We close with recommendations for future studies.

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80 to 150 Hz), subcortical/cortical slow-wave activity (SWA, 0.5 to 4 Hz), and sleep spindles (SP, 7 to 15 Hz). However, the precise role of these interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, and temporal and frontal cortices to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high-frequency activity (HFA, 70 to 200 Hz), a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical SWA or SP. Finally, local cortical SWA phase offsets and SWR amplitudes predicted functional connectivity between the frontal and temporal cortex during individual SWRs. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

Study Objectives Aerobic fitness (AF) and sleep are major determinants of health in adolescents and impact neurocognitive and psychological development. However, little is known about the interactions between AF and sleep during the developmental transition experienced across adolescence. This study aimed to consider the relationships between AF and habitual sleep patterns and sleep neurophysiology in healthy adolescents. Methods Subjects (mean age = 14.6 ± 2.3 years old, range 11–17, 11 females) were evaluated for AF (peak VO2 assessed by ramp-type progressive cycle ergometry in the laboratory), habitual sleep duration and efficiency (7–14 days actigraphy), and topographic patterns of spectral power in slow wave, theta, and sleep spindle frequencies in non-rapid eye movement (NREM) sleep using overnight polysomnography (PSG) with high-density electroencephalography (hdEEG, 128 channels). Results Significant relationships were observed between peak VO2 and habitual bedtime (r = −0.650, p = .009) and wake-up time (r = −0.603, p = .017), with greater fitness associated with going to bed and waking up earlier. Peak VO2 significantly predicted slow oscillations (0.5–1 Hz, p = .018) and theta activity (4.5–7.5 Hz, p = .002) over anterior frontal and central derivations (p < .001 and p = .001, respectively) after adjusting for sex and pubertal development stage. Similar associations were detected for fast sleep spindle activity (13–16 Hz, p = .006), which was greater over temporo-parietal derivations. Conclusions Greater AF was associated with a more mature pattern of topographically-specific features of sleep EEG known to support neuroplasticity and cognitive processes and which are dependent on prefrontal cortex and hippocampal function in adolescents and adults. AF was also correlated with a smaller behavioral sleep phase delay commonly seen during adolescence.

Hippocampal-dependent memory consolidation during sleep is hypothesized to depend on the synchronization of distributed neuronal ensembles, organized by the hippocampal sharp-wave ripples (SWRs, 80-150 Hz) and subcortical/cortical slow-waves (0.5-4 Hz). However, the precise role of SWR-slow-wave interactions in synchronizing subcortical/cortical neuronal activity is unclear. Here, we leverage intracranial electrophysiological recordings from the human hippocampus, amygdala, temporal and frontal cortices, to examine activity modulation and cross-regional coordination during SWRs. Hippocampal SWRs are associated with widespread modulation of high frequency activity (HFA; 70-200 Hz) a measure of local neuronal activation. This peri-SWR HFA modulation is predicted by the coupling between hippocampal SWRs and local subcortical/cortical slow-waves. Finally, local cortical slow-wave phase offsets during SWRs predicted functional connectivity between the frontal and temporal cortex. These findings suggest a selection mechanism wherein hippocampal SWR and cortical slow-wave synchronization governs the transient engagement of distributed neuronal populations supporting hippocampal-dependent memory consolidation.

Summary Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [ 1 , 2 , 3 ]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) provide future forecasting sensitivity to the rate of Aβ accumulation over subsequent years. A cohort of clinically normal older adults was assessed using objective sleep polysomnography in combination with longitudinal tracking of Aβ accumulation with [11C]PiB positron emission tomography (PET) imaging. Both the proportion of NREM SWA below 1 Hz and the measure of sleep efficiency predicted the speed (slope) of subsequent Aβ deposition over time, and these associations remained robust when taking into account additional cofactors of interest (e.g., age, sex, sleep apnea). Moreover, these measures were specific, such that no other macro- and microphysiological architecture metrics of sleep demonstrated such sensitivity. Our data support the proposal that objective sleep markers could be part of a set of biomarkers that statistically forecast the longitudinal trajectory of cortical Aβ deposition in the human brain. Sleep may therefore represent a potentially affordable, scalable, repeatable, and non-invasive tool for quantifying of Aβ pathological progression, prior to cognitive symptoms of Alzheimer’s disease (AD).

Introduction Aerobic fitness facilitates brain synaptic plasticity, which influences global and local sleep expression. While it is known that sleep patterns/behavior and non-rapid eye movement (NREM) sleep slow wave activity (SWA) tracks brain maturation, little is known about how aerobic fitness and sleep interact during development in youth. The aim of this pilot was to characterize relationships among aerobic fitness, measures of global/local sleep expression, and habitual sleep patterns in children and adolescents. We hypothesized that greater aerobic fitness would be associated with better sleep quality, indicated by increased SWA. Methods 20 adolescents (mean age=14.6±2.3 years old, range 11-17, 11 females) were evaluated for AF (peak VO2 assessed by ramp-type progressive cycle ergometry in the laboratory), habitual sleep duration and efficiency (continuous 7-14 day actigraphy with sleep diary), and topographic patterns of spectral power in slow wave, theta, and sleep spindle frequency ranges in non-rapid eye movement (NREM) sleep using overnight polysomnography with high-density electroencephalography (hdEEG, 128 channels). Results Significant relationships were observed between peak VO2 and habitual bedtime (r=-0.604, p=0.013) and wake-up time (r=-0.644, p=0.007), with greater fitness associated with an earlier sleep schedule (going to bed and waking up earlier). Peak VO2 was a significant predictor of slow oscillations (0.5-1Hz, p=0.018) and theta activity (4.5-7.5Hz, p=0.002) over anterior frontal and central derivations (p Conclusion Greater AF was associated with earlier habitual sleep times and with enhanced expression of developmentally-relevant sleep oscillations during NREM sleep. These data suggest that AF may 1) minimize the behavioral sleep delay commonly seen during adolescence, and 2) impact topographically-specific features of sleep physiology known to mechanistically support neuroplasticity and cognitive processes which are dependent on prefrontal cortex and hippocampal function in adolescents and adults. Support (if any) NCATS grant #UL1TR001414 & PERC Systems Biology Fund

See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.

Introduction Aerobic fitness facilitates brain synaptic plasticity, which influences global and local sleep expression. While it is known that sleep patterns/behavior and non-rapid eye movement (NREM) sleep slow wave activity (SWA) tracks brain maturation, little is known about how aerobic fitness and sleep interact during growth and development in children and adolescents. The aim of this pilot study was to characterize relationships among aerobic fitness, measures of global/local sleep expression, and habitual sleep patterns in children and adolescents. We hypothesized that greater aerobic fitness would be associated with better sleep quality, indicated by increased SWA. Methods Twenty healthy youth (11-17 years-old, 11 female) were evaluated during summer vacation (no school schedule constraints). Aerobic fitness (VO2peak) was measured using ramp-type progressive cycle ergometry, habitual sleep (i.e., sleep-time consistency and circadian activity patterns) was assessed with 7-day actigraphy, and ad lib sleep was evaluated during overnight polysomnography (PSG) with high-density electroencephalography (hdEEG; 128 channels). Spectral analysis was implemented to quantify SWA (0.5-4.5Hz). Data were analyzed using linear regression analyses and exploratory independent samples t-tests. Results Negative correlations were observed between VO2peak and sleep measures including sleep-time consistency (partial r=-0.53, p=0.045) and timing/acrophase of the circadian activity rhythm (partial r=-0.64, p=0.01) while controlling for sex and age. Additionally, after accounting for Tanner stage and sex, data demonstrated significant effects in SWA at frontal derivations (p=0.024) between low and high fitness levels at topographically specific and meaningful EEG derivations, e.g. over frontal cortex. Conclusion These results suggest that children and adolescents with greater fitness have less variability in sleep-times (improved sleep consistency), tend to have a more advanced circadian activity phase (i.e., go to sleep earlier), and express greater frontal SWA, supporting the hypothesis that fitness is associated with improved local and global sleep quality. Future research with larger samples is necessary to further evaluate these relationships, and to determine if interventions that improve fitness also improve sleep and related brain plasticity. Support NCATS grant #UL1TR001414 & PERC Systems Biology Fund

Introduction Chronic inflammation in aging is independently associated with tau burden and sleep disruption, though the mechanism linking inflammation with sleep disruption remains unknown. Recent evidence associates tau burden with deficits in local expression of sleep spindles and slow wave activity (SWA). Here we test the hypothesis that age-related central inflammation disrupts local sleep by influencing tau pathology. Methods Cognitively asymptomatic older adults from the Wisconsin Alzheimer’s Disease Research Center underwent overnight polysomnography with high-density electroencephalography (hdEEG; 256 channels) at the University of Wisconsin-Madison (n=33, 61.9±6.7 years, 23 female). EEG data were subjected to multitaper spectral analysis (0.5-40Hz) to yield topographic maps of SWA (SWA1:0.5-1Hz, SWA2:1-4.5Hz) and spindle (sigma1:11-13Hz; sigma2:13-16Hz) power during NREM sleep. Cerebrospinal fluid assay-based measurements of YKL-40 (indicating glial activation), phosphorylated tau (Ptau), and total tau (Ttau), were correlated with SWA and sigma topographical power employing Holm-Bonferroni correction. Multiple linear regression models were implemented controlling for age, apnea-hypopnea index (AHI), and sex at significant derivations. Finally, Sobel testing was employed to assess whether tau burden mediated YKL-40-sleep associations. Results Age was associated with YKL-40 (r=0.53, p=0.002), and YKL-40 was associated with both Ptau (r=0.66, p Conclusion These results suggest that age-related increases in central glial activation may disrupt local expression of fast spindles by increasing tau burden, highlighting a potential role for chronic inflammation in sleep deficits observed in aging and Alzheimer’s disease. Support Supported by R56 AG052698, P50AG033514

How are memories transferred from short-term to long-term storage? Systems-level memory consolidation is thought to be dependent on the coordinated interplay of cortical slow waves, thalamo-cortical sleep spindles and hippocampal ripple oscillations. However, it is currently unclear how the selective interaction of these cardinal sleep oscillations is organized to support information reactivation and transfer. Here, using human intracranial recordings, we demonstrate that the prefrontal cortex plays a key role in organizing the ripple-mediated information transfer during non-rapid eye movement (NREM) sleep. We reveal a temporally precise form of coupling between prefrontal slow-wave and spindle oscillations, which actively dictates the hippocampal-neocortical dialogue and information transfer. Our results suggest a model of the human sleeping brain in which rapid bidirectional interactions, triggered by the prefrontal cortex, mediate hippocampal activation to optimally time subsequent information transfer to the neocortex during NREM sleep., How are memories transferred from short-term to long-term storage? Here, the authors show that during deep (NREM) sleep, the prefrontal cortex initiates rapid, bidirectional interactions to trigger information transfer from the hippocampus to the neocortex.

Deep non-rapid eye movement sleep (NREM) and general anesthesia with propofol are prominent states of reduced arousal linked to the occurrence of synchronized oscillations in the electroencephalogram (EEG). Although rapid eye movement (REM) sleep is also associated with diminished arousal levels, it is characterized by a desynchronized, ‘wake-like’ EEG. This observation implies that reduced arousal states are not necessarily only defined by synchronous oscillatory activity. Using intracranial and surface EEG recordings in four independent data sets, we demonstrate that the 1/f spectral slope of the electrophysiological power spectrum, which reflects the non-oscillatory, scale-free component of neural activity, delineates wakefulness from propofol anesthesia, NREM and REM sleep. Critically, the spectral slope discriminates wakefulness from REM sleep solely based on the neurophysiological brain state. Taken together, our findings describe a common electrophysiological marker that tracks states of reduced arousal, including different sleep stages as well as anesthesia in humans., eLife digest Electroencephalogram (EEG for short) is a widespread technique that helps to monitor the electrical activity of the brain. In particular, it can be used to examine, recognize and compare different states of brain consciousness such as sleep, wakefulness or general anesthesia. Yet, during rapid eye movement sleep (the sleep phase in which dreaming occurs), the electrical activity of the brain is similar to the one recorded during wakefulness, making it difficult to distinguish these states based on EEG alone. EEG records brain activity in the shape of rhythmic waves whose frequency, shape and amplitude vary depending on the state of consciousness. In the EEG signal from the human brain, the higher frequency waves are weaker than the low-frequency waves: a measure known as spectral slope reflects the degree of this difference in the signal strength. Previous research suggests that spectral slope can be used to distinguish wakefulness from anesthesia and non-REM sleep. Here, Lendner et al. explored whether certain elements of the spectral slope could also discern wakefulness from all states of reduced arousal. EEG readings were taken from patients and volunteers who were awake, asleep or under anesthesia, using electrodes placed either on the scalp or into the brain. Lendner et al. found that the spectral slope could distinguish wakefulness from anesthesia, deep non-REM and REM sleep. The changes in the spectral slope during sleep could accurately track the degree of arousal with great temporal precision and across a wide range of time scales. This method means that states of consciousness can be spotted just from a scalp EEG. In the future, this approach could be embedded into the techniques used for monitoring sleep or anesthesia during operations; it could also be harnessed to monitor other low-response states, such as comas.

How do we remember emotional events? While emotion often leads to vivid recollection, the precision of emotional memories can be degraded, especially when discriminating among overlapping experiences in memory (i.e., pattern separation). Communication between the amygdala and the hippocampus has been proposed to support emotional memory, but the exact neural mechanisms remain unclear. Here, we used intracranial recordings in pre-surgical epilepsy patients to show that successful pattern separation of emotional stimuli is associated with theta band (3-7Hz)-coordinated bidirectional interactions between the amygdala and the hippocampus. In contrast, discrimination errors (i.e., failure to discriminate similar stimuli) were associated with alpha band (7-13Hz)-coordinated unidirectional influence from the amygdala to the hippocampus. These findings imply that alpha band synchrony may impair discrimination of similar emotional events via the amygdala-hippocampal directional coupling, which suggests a target for treatments of psychiatric conditions such as post-traumatic stress disorder, in which aversive experiences are often overgeneralized.

Introduction The prevalence of obstructive sleep apnea (OSA) rises with age, leading to increased dementia risk and memory decline. However, it remains unclear which OSA features drive this relationship. Here, we examine associations between verbal memory and multiple OSA features in healthy older adults. Methods 58 cognitively asymptomatic adults (61.4±6.3 years; 38 females) underwent polysomnography (PSG) and the Rey Auditory Verbal Learning Test (RAVLT; 0.2±0.5 years between assessments). OSA measures included apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and desaturation index in both NREM and REM sleep. RAVLT measures included total learning (sum of trials 1–5), short-delayed recall, and long-delayed recall. Pearson correlations with FDR correction were calculated between OSA-related measures and RAVLT. Multiple regression was then used to adjust for OSA features in other sleep stages (i.e., REM versus NREM), age, sex, time between PSG and neuropsychological assessments, years of education, and APOE4 status. We also explored whether age moderated these relationships. Results REM RDI is negatively associated with RAVLT total learning (r=-0.31, p Conclusion These findings demonstrate that REM OSA features in particular contribute to poor verbal memory encoding and retrieval, especially at older ages. Verbal memory decline has been predictive of conversion to Alzheimer’s disease (AD). Future studies including brain imaging, AD biomarkers, REM sleep oscillations, and comprehensive neuropsychological testing may elucidate the underlying mechanisms linking REM OSA features to memory decline and dementia risk. Support (if any) This research was supported by R56 AG052698 and P50AG033514.

Introduction Aerobic fitness facilitates brain synaptic plasticity, which influences global and local sleep expression. While it is known that sleep patterns/behavior and non-rapid eye movement (NREM) sleep slow wave activity (SWA) tracks brain maturation, little is known about how aerobic fitness and sleep interact during development in youth. The aim of this pilot was to characterize relationships among aerobic fitness, measures of global/local sleep expression, and habitual sleep patterns in children and adolescents. We hypothesized that greater aerobic fitness would be associated with better sleep quality, indicated by increased SWA. Methods 20 adolescents (mean age=14.6±2.3 years old, range 11-17, 11 females) were evaluated for AF (peak VO2 assessed by ramp-type progressive cycle ergometry in the laboratory), habitual sleep duration and efficiency (continuous 7-14 day actigraphy with sleep diary), and topographic patterns of spectral power in slow wave, theta, and sleep spindle frequency ranges in non-rapid eye movement (NREM) sleep using overnight polysomnography with high-density electroencephalography (hdEEG, 128 channels). Results Significant relationships were observed between peak VO2 and habitual bedtime (r=-0.604, p=0.013) and wake-up time (r=-0.644, p=0.007), with greater fitness associated with an earlier sleep schedule (going to bed and waking up earlier). Peak VO2 was a significant predictor of slow oscillations (0.5-1Hz, p=0.018) and theta activity (4.5-7.5Hz, p=0.002) over anterior frontal and central derivations (p Conclusion Greater AF was associated with earlier habitual sleep times and with enhanced expression of developmentally-relevant sleep oscillations during NREM sleep. These data suggest that AF may 1) minimize the behavioral sleep delay commonly seen during adolescence, and 2) impact topographically-specific features of sleep physiology known to mechanistically support neuroplasticity and cognitive processes which are dependent on prefrontal cortex and hippocampal function in adolescents and adults. Support (if any) NCATS grant #UL1TR001414 & PERC Systems Biology Fund

Introduction Mnemonic discrimination, the ability to differentiate novel and highly similar but not identical stimuli, is negatively associated with sleep deprivation and depression. Depression is additionally associated with increased discrimination specifically for negative emotional stimuli. While sleep and circadian activity rhythm (CAR) disturbances are common in depression and have been reported to have negative impact on hippocampal-dependent memories, their relationship with emotional discrimination has yet to be investigated. Methods As part of a larger study, 14 patients with DSM-5 major depressive disorder (22.9±4.1 years, 71.4% female) and 13 healthy controls (29.4±8.5 years, 61.5% female) were evaluated with wrist-actigraphy (7–14 days) and completed an emotional discrimination task. Lure discrimination index (LDI) for each emotion type (i.e., negative, neutral, and positive) was calculated to indicate how well participants discriminated among highly similar lures. Actigraphy-derived sleep parameters included total sleep time (TST), sleep efficiency (SE), and midsleep time. Minute-by-minute actigraphy-derived activity counts were used to characterize CAR and parametrized using cosinor analysis and Generalized Additive Models (GAM) deriving the rhythm Acrophase, Amplitude, UP time, and DOWN time. A repeated measures ANOVA (within-subjects: emotion, between-subjects: group) assessed whether mnemonic discrimination differed between patients with MDD and controls. Partial correlations examined the association between sleep and CAR parameters with mnemonic discrimination, while controlling for age, state anxiety, depression severity, TST, and groups. Results We found a significant effect of emotion [F(2,90)=3.25, p=0.043], where neutral information was remembered better than emotional information (p’s Conclusion Delayed CAR, characterized by latter midsleep time and delayed acrophase and peak time of the morning activity, is associated with increased discrimination for negative emotional information, independent of depressive symptom severity. Future studies are needed to replicate these findings and further explore the potential cognitive benefits of adjunctive interventions addressing sleep/CAR in mitigating symptoms of depression. Support (if any) National Institutes of Health R01 432MH102392.

Serotonergic agonist psilocybin is a psychedelic with antidepressant potential. Sleep may interact with psilocybin’s antidepressant properties like other antidepressant drugs via induction of neuroplasticity. The main aim of the study was to evaluate the effect of psilocybin on sleep architecture on the night after psilocybin administration. Regarding the potential antidepressant properties, we hypothesized that psilocybin, similar to other classical antidepressants, would reduce rapid eye movement (REM) sleep and prolong REM sleep latency. Moreover, we also hypothesized that psilocybin would promote slow-wave activity (SWA) expression in the first sleep cycle, a marker of sleep-related neuroplasticity. Twenty healthy volunteers (10 women, age 28–53) underwent two drug administration sessions, psilocybin or placebo, in a randomized, double-blinded design. Changes in sleep macrostructure, SWA during the first sleep cycle, whole night EEG spectral power across frequencies in non-rapid eye movement (NREM) and REM sleep, and changes in subjective sleep measures were analyzed. The results revealed prolonged REM sleep latency after psilocybin administration and a trend toward a decrease in overall REM sleep duration. No changes in NREM sleep were observed. Psilocybin did not affect EEG power spectra in NREM or REM sleep when examined across the whole night. However, psilocybin suppressed SWA in the first sleep cycle. No evidence was found for sleep-related neuroplasticity, however, a different dosage, timing, effect on homeostatic regulation of sleep, or other mechanisms related to antidepressant effects may play a role. Overall, this study suggests that potential antidepressant properties of psilocybin might be related to changes in sleep.

Older adults with mild cognitive impairment (MCI) are at-risk of developing dementia, particularly Alzheimer's disease. While some research suggests that alterations in sleep architecture may mediate cognitive decline, the nature and magnitude of changes to sleep macro- (sleep stages) and micro-architecture (electroencephalography (EEG) oscillations) in MCI is not yet clear. This study aimed to systematically review and meta-analyse case-control studies objectively measuring sleep in MCI. A systematic search was conducted using PubMed, Scopus, Web of Science, Embase and Psycinfo databases and after review, a total of 10 studies met inclusion criteria. Of these, all reported sleep macro-architecture and four reported micro-architecture outcomes. A combined total of 430 participants (209 with and 221 without MCI) underwent objective sleep assessments in the included full text articles. Findings show that compared to healthy controls, those with MCI have pronounced changes in sleep macro-architecture with greater wake after sleep onset, reduced total sleep time, lower sleep efficiency, longer sleep onset latency, longer rapid eye movement sleep (REM) latency, reduced REM sleep, greater N1 sleep, and worse severity of hypoxemia. Pooling of sleep micro-architecture EEG measures was not possible due to limited studies, however reduced spindles in non-REM sleep and greater EEG slowing in REM sleep were reported.

Introduction Insufficient sleep and sedentary behavior are associated with cognitive decline. How sleep and physical activity interact to influence cognition is not fully understood. This study sought to examine whether self-reported sleep and exercise impact subjective cognitive complaints across adulthood. Methods Self-report questionnaire data from 2,744 adults (μ=56.18 yrs/old; 63.8% F; μ=16.36 yrs/edu) in the University of California Irvine Consent-to-Contact Registry were analyzed. Multiple regression models, analysis of covariance, and ordinary least squares path analysis were conducted to investigate relationships among the Cognitive Function Instrument (CFI), Medical Outcome Study Sleep Scale (MOS-SS) Subscales, and exercise frequency. All models adjusted for education, sex, age, BMI, medical comorbidities, depression, cancer diagnosis, and antidepressant usage. Individuals taking medications known to affect sleep or with a diagnosis major psychiatric illness were excluded from analyses. Results All MOS-SS Subscales significantly predicted CFI score (all p3times/week had significantly lower scores on the CFI (p Conclusion More self-reported sleep disturbance and greater daytime sleepiness are associated with more subjective cognitive complaints. Individuals who exercise more frequently report lower daytime sleepiness and higher quality sleep. The effects of exercise frequency on cognitive complaints appear to be mediated by the impact of exercise on sleep. These results suggest that sleep health may be a crucial consideration when evaluating outcomes of exercise-based therapies aimed at delaying the onset of cognitive impairment. Support The C2C registry was made possible by a donation from HCP, Inc. and is supported by NIA AG016573 and NCATS UL1 TR001414.

Introduction The prefrontal cortex, an area known for executive functioning (including inhibition and self-monitoring) develops during childhood and adolescents, with a pattern of posterior to anterior brain development. Slow-wave activity (SWA) in NREM sleep, tracks brain development with high SWA power migrating from occipital to frontal region as brain maturation occurs. This pilot study aimed to examine whether slow wave topography is correlated with executive function in youth. Methods Seventeen healthy children and adolescents (ages 11-17; 10 females) underwent overnight polysomnography (PSG) with high-density electroencephalography (hdEEG). Behavior Rating Inventory of Executive Function (BRIEF) was administered to assess executive function. SWA (SWA1: 0.5-1 Hz; SWA2: 1-4.5 Hz) and spindle (slow sigma: 11-13 Hz; fast sigma: 13-16 Hz) activity was analyzed with spectral analysis using Welch’s method. BRIEF subscales of inhibition and monitor were correlated with SWA and sigma power across all derivations, with Holm-Bonferroni correction (126 channels). Significant derivations were then controlled for sex and self-reported Tanner stage using multiple regression Results BRIEF-Inhibition scale (i.e., ability to repress impulsivity) and SWA1 in anterior frontal derivations were negatively correlated (R2=0.58, p=0.047 corrected). BRIEF-Monitor scale (i.e., self-perception of one’s own behavior and interpersonal awareness) was negatively correlated with fast sigma in anterior frontal derivations (R2=0.65, p=0.013 corrected). These associations were significant after controlling for sex and Tanner stage. Conclusion These results support the hypothesis that NREM sleep oscillations are associated with executive function and reflect changes in neuroplasticity related to “back-to-front” brain maturation. Future longitudinal studies should combine multi-modal neuroimaging of brain structure and local sleep with comprehensive assessments of executive function to evaluate the possible link between local sleep and development of higher-order cognition in frontal brain regions in youth. Support NCATS grant #UL1TR001414 & PERC Systems Biology Fund

BACKGROUND: Several lines of research support associations between sleep and cognition in older adults. However, there is a paucity of data regarding sleep and cognition in nonagenarians and centenarians. AIMS: The current study examined self-reported sleep quantity and sleep quality in relation to hippocampal volume and cognition in adults aged 90 and older. METHODS: A total of 144 participants of The 90+ Study completed The Medical Outcomes Study sleep questionnaire. Participants reported subjective sleep duration in hours and three sleep quality factors: sleep problems, adequacy, and somnolence. Neuropsychological assessments of memory, global cognition, language, and executive function were completed, on average, 61 days from the questionnaire. Hippocampal volume on 3T MRI, adjusted for intracranial volume, was obtained in 82 participants. We performed multiple linear regressions, controlling for age, sex, education, sleep medication, and depression, to examine sleep characteristics in relation to hippocampal volume and cognitive performance in all subjects and then stratified by cognition. RESULTS: Sleep duration >8 hours was associated with lower scores in tests of global cognition, memory, and executive function compared to sleep duration of 7–8 hours when collapsing across cognitive status, but only with memory in cognitively impaired subjects, and not in cognitively normal subjects. DISCUSSION AND CONCLUSIONS: Long sleep duration is associated with poorer global cognition, memory, and executive function in the oldest-old, and is only associated with memory in cognitively impaired oldest-old. Additional research is necessary to determine if sleep duration is a risk factor or a result of poor cognition in advanced age.

How does a lack of sleep affect our brains? In contrast to the benefits of sleep, frameworks exploring the impact of sleep loss are relatively lacking. Importantly, the effects of sleep deprivation (SD) do not simply reflect the absence of sleep and the benefits attributed to it; rather, they reflect the consequences of several additional factors, including extended wakefulness. With a focus on neuroimaging studies, we review the consequences of SD on attention and working memory, positive and negative emotion, and hippocampal learning. We explore how this evidence informs our mechanistic understanding of the known changes in cognition and emotion associated with SD, and the insights it provides regarding clinical conditions associated with sleep disruption.

Older adults do not sleep as well as younger adults. Why? What alterations in sleep quantity and quality occur as we age, and are there functional consequences? What are the underlying neural mechanisms that explain age-related sleep disruption? This review tackles these questions. First, we describe canonical changes in human sleep quantity and quality in cognitively normal older adults. Second, we explore the underlying neurobiological mechanisms that may account for these human sleep alterations. Third, we consider the functional consequences of age-related sleep disruption, focusing on memory impairment as an exemplar. We conclude with a discussion of a still-debated question: do older adults simply need less sleep, or rather, are they unable to generate the sleep that they still need?

© The Author 2013. Published by Oxford University Press. All rights reserved. A hallmark feature of cognitive aging is a decline in the ability to form new memories. Parallel to these cognitive impairments are marked disruptions in sleep physiology. Despite recent evidence in young adults establishing a role for sleep spindles in restoring hippocampaldependent memory formation, the possibility that disrupted sleep physiology contributes to age-related decline in hippocampaldependent learning remains unknown. Here, we demonstrate that reduced prefrontal sleep spindles by over 40% in older adults statistically mediates the effects of old age on next day episodic learning, such that the degree of impaired episodic learning is explained by the extent of impoverished prefrontal sleep spindles. In addition, prefrontal spindles significantly predicted the magnitude of impaired next day hippocampal activation, thereby determining the influence of spindles on post-sleep learning capacity. These data support the hypothesis that disrupted sleep physiology contributes to age-related cognitive decline in later life, the consequence of which has significant treatment intervention potential.

Aging has independently been associated with regional brain atrophy, reduced slow wave activity (SWA) during non-rapid eye movement (NREM) sleep and impaired long-term retention of episodic memories. However, whether the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. We found that age- related medial prefrontal cortex (mPFC) gray-matter atrophy was associated with reduced NREM SWA in older adults, the extent to which statistically mediated the impairment of overnight sleep-dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex functional connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represents a contributing factor to age-related cognitive decline in later life.

Sleep disruption appears to be a core component of Alzheimer's disease (AD) and its pathophysiology. Signature abnormalities of sleep emerge before clinical onset of AD. Moreover, insufficient sleep facilitates accumulation of amyloid-β (Aβ), potentially triggering earlier cognitive decline and conversion to AD. Building on such findings, this review has four goals: evaluating (i) associations and plausible mechanisms linking non-rapid-eye-movement (NREM) sleep disruption, Aβ, and AD; (ii) a role for NREM sleep disruption as a novel factor linking cortical Aβ to impaired hippocampus-dependent memory consolidation; (iii) the potential diagnostic utility of NREM sleep disruption as a new biomarker of AD; and (iv) the possibility of sleep as a new treatment target in aging, affording preventative and therapeutic benefits.

The coupled interaction between slow-wave oscillations and sleep spindles during non-rapid-eye-movement (NREM) sleep has been proposed to support memory consolidation. However, little evidence in humans supports this theory. Moreover, whether such dynamic coupling is impaired as a consequence of brain aging in later life, contributing to cognitive and memory decline, is unknown. Combining electroencephalography (EEG), structural MRI, and sleep-dependent memory assessment, we addressed these questions in cognitively normal young and older adults. Directional cross-frequency coupling analyses demonstrated that the slow wave governs a precise temporal coordination of sleep spindles, the quality of which predicts overnight memory retention. Moreover, selective atrophy within the medial frontal cortex in older adults predicted a temporal dispersion of this slow wave-spindle coupling, impairing overnight memory consolidation and leading to forgetting. Prefrontal-dependent deficits in the spatiotemporal coordination of NREM sleep oscillations therefore represent one pathway explaining age-related memory decline.

One function of spatial attention is to enable goal-directed interactions with the environment through the allocation of neural resources to motivationally relevant parts of space. Studies have shown that responses are enhanced when spatial attention is predictively biased towards locations where significant events are expected to occur. Previous studies suggest that the ability to bias attention predictively is related to posterior cingulate cortex (PCC) activation [Small, D.M., et al., 2003. The posterior cingulate and medial prefrontal cortex mediate the anticipatory allocation of spatial attention. Neuroimage 18, 633–41]. Sleep deprivation (SD) impairs selective attention and reduces PCC activity [Thomas, M., et al., 2000. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J. Sleep Res. 9, 335–352]. Based on these findings, we hypothesized that SD would affect PCC function and alter the ability to predictively allocate spatial attention. Seven healthy, young adults underwent functional magnetic resonance imaging (fMRI) following normal rest and 34–36 h of SD while performing a task in which attention was shifted in response to peripheral targets preceded by spatially informative (valid), misleading (invalid), or uninformative (neutral) cues. When rested, but not when sleep-deprived, subjects responded more quickly to targets that followed valid cues than those after neutral or invalid cues. Brain activity during validly cued trials with a reaction time benefit was compared to activity in trials with no benefit. PCC activation was greater during trials with a reaction time benefit following normal rest. In contrast, following SD, reaction time benefits were associated with activation in the left intraparietal sulcus, a region associated with receptivity to stimuli at unexpected locations. These changes may render sleep-deprived individuals less able to anticipate the locations of upcoming events, and more susceptible to distraction by stimuli at irrelevant locations.