Total Sleep Deprivation Increases Brain Age Prediction Reversibly in Multisite Samples of Young Healthy Adults.

Sleep loss pervasively affects the human brain at multiple levels. Age-related changes in several sleep characteristics indicate that reduced sleep quality is a frequent characteristic of aging. Conversely, sleep disruption may accelerate the aging process, yet it is not known what will happen to the age status of the brain if we can manipulate sleep conditions. To tackle this question, we used an approach of brain age to investigate whether sleep loss would cause age-related changes in the brain. We included MRI data of 134 healthy volunteers (mean chronological age of 25.3 between the age of 19 and 39 years, 42 females/92 males) from five datasets with different sleep conditions. Across three datasets with the condition of total sleep deprivation (>24 h of prolonged wakefulness), we consistently observed that total sleep deprivation increased brain age by 1-2 years regarding the group mean difference with the baseline. Interestingly, after one night of recovery sleep, brain age was not different from baseline. We also demonstrated the associations between the change in brain age after total sleep deprivation and the sleep variables measured during the recovery night. By contrast, brain age was not significantly changed by either acute (3 h time-in-bed for one night) or chronic partial sleep restriction (5 h time-in-bed for five continuous nights). Together, the convergent findings indicate that acute total sleep loss changes brain morphology in an aging-like direction in young participants and that these changes are reversible by recovery sleep.SIGNIFICANCE STATEMENT Sleep is fundamental for humans to maintain normal physical and psychological functions. Experimental sleep deprivation is a variable-controlling approach to engaging the brain among different sleep conditions for investigating the responses of the brain to sleep loss. Here, we quantified the response of the brain to sleep deprivation by using the change of brain age predictable with brain morphologic features. In three independent datasets, we consistently found increased brain age after total sleep deprivation, which was associated with the change in sleep variables. Moreover, no significant change in brain age was found after partial sleep deprivation in another two datasets. Our study provides new evidence to explain the brainwide effect of sleep loss in an aging-like direction.

A genetic variation in the adenosine A2A receptor gene contributes to variability in oscillatory alpha power in wake and sleep EEG and A1 adenosine receptor availability in the human brain.

The EEG alpha rhythm (∼ 8-13 Hz) is one of the most salient human brain activity rhythms, modulated by the level of attention and vigilance and related to cerebral energy metabolism. Spectral power in the alpha range in wakefulness and sleep strongly varies among individuals based on genetic predisposition. Knowledge about the underlying genes is scarce, yet small studies indicated that the variant rs5751876 of the gene encoding A2A adenosine receptors (ADORA2A) may contribute to the inter-individual variation. The neuromodulator adenosine is directly linked to energy metabolism as product of adenosine tri-phosphate breakdown and acts as a sleep promoting molecule by activating A1 and A2A adenosine receptors. We performed sleep and positron emission tomography studies in 59 healthy carriers of different rs5751876 alleles, and quantified EEG oscillatory alpha power in wakefulness and sleep, as well as A1 adenosine receptor availability with 18F-CPFPX. Oscillatory alpha power was higher in homozygous C-allele carriers (n = 27, 11 females) compared to heterozygous and homozygous carriers of the T-allele (n(C/T) = 23, n(T/T) = 5, 13 females) (F(18,37) = 2.35, p = 0.014, Wilk's Λ = 0.487). Furthermore, a modulatory effect of ADORA2A genotype on A1 adenosine receptor binding potential was found across all considered brain regions (F(18,40) = 2.62, p = 0.006, Wilk's Λ = 0.459), which remained significant for circumscribed occipital region of calcarine fissures after correction for multiple comparisons. In female participants, a correlation between individual differences in oscillatory alpha power and A1 receptor availability was observed. In conclusion, we confirmed that a genetic variant of ADORA2A affects individual alpha power, while a direct modulatory effect via A1 adenosine receptors in females is suggested.

Cerebral A1 adenosine receptor availability in female and male participants and its relationship to sleep.

The neuromodulator adenosine and its receptors are mediators of sleep-wake regulation which is known to differ between sexes. We, therefore, investigated sex differences in A1 adenosine receptor (A1AR) availability in healthy human subjects under well-rested conditions using [18F]CPFPX and positron emission tomography (PET). [18F]CPFPX PET scans were acquired in 50 healthy human participants (20 females; mean age ± SD 28.0 ± 5.3 years). Mean binding potential (BPND; Logan's reference tissue model with cerebellum as reference region) and volume of distribution (VT) values were calculated in 12 and 15 grey matter brain regions, respectively. [18F]CPFPX BPND was higher in females compared to males in all investigated brain regions (p < 0.025). The largest differences were found in the pallidum and anterior cingulate cortex, where mean BPND values were higher by 29% in females than in males. In females, sleep efficiency correlated positively and sleep latency negatively with BPND in most brain regions. VT values did not differ between sexes. Sleep efficiency correlated positively with VT in most brain regions in female participants. In conclusion, our analysis gives a first indication for potential sex differences in A1AR availability even under well-rested conditions. A1AR availability as measured by [18F]CPFPX BPND is higher in females compared to males. Considering the involvement of adenosine in sleep-wake control, this finding might partially explain the known sex differences in sleep efficiency and sleep latency.

Adverse interaction effects of chronic and acute sleep deficits on spatial working memory but not on verbal working memory or declarative memory.

The accumulation of chronic sleep deficits combined with acute sleep loss is common in shift workers and increases the risk of errors and accidents. We investigated single and combined effects of chronic and acute sleep loss and recovery sleep on working memory performance (N-back task) and on overnight declarative memory recall (paired-associate lists) in 36 healthy participants. After baseline measurements, the chronic sleep restriction group (n = 21; mean [SD] age 26 [4] years) underwent 5 nights of sleep restriction (5-hr time in bed [TIB]), whereas the control group (n = 15; mean [SD] age 28 [6] years) had 8-hr TIB during those nights. Afterwards, both groups spent 1 night with 8-hr TIB prior to acute sleep deprivation for 38 hr, and a final recovery night (10-hr TIB). Chronic sleep restriction decreased spatial N-back performance compared to baseline (omissions: p = .001; sensitivity: p = .012), but not letter N-back performance or word-pair recall. Acute sleep deprivation impaired spatial N-back performance more in the chronic sleep restriction group than in the control group (interaction between group and time awake: p ≤ .02). No group differences during acute sleep loss appeared in letter N-back performance or word recall. It is concluded that chronic sleep loss, even when followed by a night of recovery sleep, increases the vulnerability to impairments in spatial working memory during subsequent acute sleep loss. Verbal working memory and declarative memory were not affected by restricted sleep.

Cognitive impairments by alcohol and sleep deprivation indicate trait characteristics and a potential role for adenosine A1 receptors.

Trait-like differences in cognitive performance after sleep loss put some individuals more at risk than others, the basis of such disparities remaining largely unknown. Similarly, interindividual differences in impairment in response to alcohol intake have been observed. We tested whether performance impairments due to either acute or chronic sleep loss can be predicted by an individual's vulnerability to acute alcohol intake. Also, we used positron emission tomography (PET) to test whether acute alcohol infusion results in an up-regulation of cerebral A1 adenosine receptors (A1ARs), similar to the changes previously observed following sleep deprivation. Sustained attention in the psychomotor vigilance task (PVT) was tested in 49 healthy volunteers (26 ± 5 SD years; 15 females) (i) under baseline conditions: (ii) after ethanol intake, and after either (iii) total sleep deprivation (TSD; 35 hours awake; n = 35) or (iv) partial sleep deprivation (PSD; four nights with 5 hours scheduled sleep; n = 14). Ethanol- versus placebo-induced changes in cerebral A1AR availability were measured in 10 healthy male volunteers (31 ± 9 years) with [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX) PET. Highly significant correlations between the performance impairments induced by ethanol and sleep deprivation were found for various PVT parameters, including mean speed (TSD, r = 0.62; PSD, r = 0.84). A1AR availability increased up to 26% in several brain regions with ethanol infusion. Our studies revealed individual trait characteristics for being either vulnerable or resilient to both alcohol and to sleep deprivation. Both interventions induce gradual increases in cerebral A1AR availability, pointing to a potential common molecular response mechanism.

Impact of acute sleep deprivation on dynamic functional connectivity states.

Sleep deprivation (SD) could amplify the temporal fluctuation of spontaneous brain activities that reflect different arousal levels using a dynamic functional connectivity (dFC) approach. Therefore, we intended to evaluate the test-retest reliability of dFC characteristics during rested wakefulness (RW), and to explore how the properties of these dynamic connectivity states were affected by extended durations of acute sleep loss (28/52 hr). We acquired resting-state fMRI and neuropsychological datasets in two independent studies: (a) twice during RW and once after 28 hr of SD (n = 15) and (b) after 52 hr of SD and after 14 hr of recovery sleep (RS; n = 14). Sliding-window correlations approach was applied to estimate their covariance matrices and corresponding three connectivity states were generated. The test-retest reliability of dFC properties demonstrated mean dwell time and fraction of connectivity states were reliable. After SD, the mean dwell time of a specific state, featured by strong subcortical-cortical anticorrelations, was significantly increased. Conversely, another globally hypoconnected state was significantly decreased. Subjective sleepiness and objective performances were separately positive and negative correlated with the increased and decreased state. Two brain connectivity states and their alterations might be sufficiently sensitive to reflect changes in the dynamics of brain mental activities after sleep loss.

Recovery sleep after extended wakefulness restores elevated A1 adenosine receptor availability in the human brain.

Adenosine and functional A1 adenosine receptor (A1AR) availability are supposed to mediate sleep-wake regulation and cognitive performance. We hypothesized that cerebral A1AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [18F]CPFPX positron emission tomography was used to quantify A1AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A1AR values after 8 h of baseline sleep from an earlier dataset. Polysomnography, cognitive performance, and sleepiness were monitored. Recovery from sleep deprivation was associated with a decrease in A1AR availability in several brain regions, ranging from 11% (insula) to 14% (striatum). A1AR availabilities after recovery did not differ from baseline sleep in the control group. The degree of performance impairment, sleepiness, and homeostatic sleep-pressure response to sleep deprivation correlated negatively with the decrease in A1AR availability. Sleep deprivation resulted in a higher A1AR availability in the human brain. The increase that was observed after 52 h of wakefulness was restored to control levels during a 14-h recovery sleep episode. Individuals with a large increase in A1AR availability were more resilient to sleep-loss effects than those with a subtle increase. This pattern implies that differences in endogenous adenosine and A1AR availability might be causal for individual responses to sleep loss.

Reestablishment of individual sleep structure during a single 14-h recovery sleep episode after 58 h of wakefulness.

Sleep structure is highly stable within individuals but different between individuals. The present study investigated robustness of the individual sleep structure to extended total sleep deprivation. Seventeen healthy men spent a baseline night (23:00-07:00 hours), 58 h of sleep deprivation and a 14-h recovery night (17:00-07:00 hours) in the laboratory. Intraclass correlation coefficients showed that the agreement between baseline and recovery with respect to the proportion of the different sleep stages increased as a function of recovery sleep duration. High values were reached for most of the sleep stages at the end of 14 h of recovery sleep (intraclass correlation coefficients between 0.38 and 0.76). If sleep duration of the recovery night is extended to 14 h, sleep stage distribution resembles that of a baseline night underlining the robustness of the individual sleep structure.

Associations between quantitative sleep EEG and subsequent cognitive decline in older women.

The pathophysiological processes of Alzheimer's dementia predate its clinical manifestation. Sleep disturbances can accelerate the aging process and are common features of dementia. This study examined whether quantitative sleep electroencephalogram changes predate the clinical development of mild cognitive impairment and/or incident dementia. We collected data from a nested case-control sample of women (mean age 83 years) from the Sleep and Cognition Study, an ancillary study to the longitudinal Study of Osteoporotic Fractures, who were characterized as cognitively normal at the time of a baseline polysomnography study (Study of Osteoporotic Fractures visit 8) based on a Mini-Mental Status Exam (MMSE) score >24. Cases (n = 85) were women who developed new mild cognitive impairment or dementia by objective cognitive testing 5 years after polysomnography. Controls were women with no mild cognitive impairment/dementia (n = 85) at baseline or at follow-up. Differences in electroencephalogram absolute and relative power density were observed between the two groups. Specifically, higher electroencephalogram power values were found in the dementia/mild cognitive impairment group, for the alpha (p = .01) and theta bands (p = .04) in non-rapid eye movement sleep, as well as alpha (p = .04) and sigma (p = .04) bands in rapid eye movement sleep. In contrast, there were no group differences in traditional polysomnography measures of sleep architecture and sleep stage distribution, as well as sleep apnea and periodic limb movement indices. Our results provide evidence for quantitative electroencephalogram changes, which precede the clinical onset of cognitive decline and the diagnosis of dementia in elderly women, and support the application of quantitative sleep electroencephalogram analysis as a promising biomarker for imminent cognitive decline.

Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness.

In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength-enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.

Passenger comfort on high-speed trains: effect of tunnel noise on the subjective assessment of pressure variations.

When passing through a tunnel, aerodynamic effects on high-speed trains may impair passenger comfort. These variations in atmospheric pressure are accompanied by transient increases in sound pressure level. To date, it is unclear whether the latter influences the perceived discomfort associated with the variations in atmospheric pressure. In a pressure chamber of the DLR-Institute of Aerospace Medicine, 71 participants (M = 28.3 years ± 8.1 SD) rated randomised pressure changes during two conditions according to a crossover design. The pressure changes were presented together with tunnel noise such that the sound pressure level was transiently elevated by either +6 dB (low noise condition) or +12 dB (high noise condition) above background noise level (65 dB(A)). Data were combined with those of a recent study, in which identical pressure changes were presented without tunnel noise (Schwanitz et al., 2013, 'Pressure Variations on a Train - Where is the Threshold to Railway Passenger Discomfort?' Applied Ergonomics 44 (2): 200-209). Exposure-response relationships for the combined data set comprising all three noise conditions show that pressure discomfort increases with the magnitude and speed of the pressure changes but decreases with increasing tunnel noise. Practitioner Summary: In a pressure chamber, we systematically examined how pressure discomfort, as it may be experienced by railway passengers, is affected by the presence of tunnel noise during pressure changes. It is shown that across three conditions (no noise, low noise (+6 dB), high noise (+12 dB)) pressure discomfort decreases with increasing tunnel noise.

Significance of time awake for predicting pilots' fatigue on short-haul flights: implications for flight duty time regulations.

European regulations restrict the duration of the maximum daily flight duty period for pilots as a function of the duty start time and the number of scheduled flights. However, late duty end times that may include long times awake are not specifically regulated. In this study, fatigue levels in pilots finishing their duty late at night (00:00-01:59 hour) were analysed and compared with pilots starting their duty early (05:00-06:59 hour). Fatigue levels of 40 commercial short-haul pilots were studied during a total of 188 flight duty periods, of which 87 started early and 22 finished late. Pilots used a small handheld computer to maintain a duty and sleep log, and to indicate fatigue levels immediately after each flight. Sleep logs were checked with actigraphy. Pilots on late-finishing flight duty periods were more fatigued at the end of their duty than pilots on early-starting flight duty periods, despite the fact that preceding sleep duration was longer by 1.1 h. Linear mixed-model regression identified time awake as a preeminent factor predicting fatigue. Workload had a minor effect. Pilots on late-finishing flight duty periods were awake longer by an average of 5.5 h (6.6 versus 1.1 h) before commencing their duty than pilots who started early in the morning. Late-finishing flights were associated with long times awake at a time when the circadian system stops promoting alertness, and an increased, previously underestimated fatigue risk. Based on these findings, flight duty limitations should consider not only duty start time, but also the time of the final landing.

Spontaneous attentional failures reflect multiplicative interactions of chronic sleep loss with acute sleep loss and circadian misalignment.

OBJECTIVES: Acute and chronic sleep loss and circadian timing interact such that, depending on their combination, small or very large performance decrements are observed in tasks of attention. Here, we tested whether such nonlinear interactions extend to a physiological measure of spontaneous visual attentional failures, indicating a fundamental principle of sleep-wake regulation. METHODS: Nine healthy volunteers completed an in-laboratory 3-week forced desynchrony protocol consisting of 12 consecutive 42.85-hour cycles with a sleep-wake ratio of 1:3.3. The protocol induced increasing chronic sleep loss, while extended wake (32.85 hours) and sleep episodes (10 hours) occurred at multiple circadian phases. Attentional failure rate was quantified from continuous electrooculograms (number of 30-second epochs with slow eye movements/h of wakefulness) as a function of time since scheduled wake (acute sleep loss), week of study (chronic sleep loss), and circadian (melatonin) phase. RESULTS: During the first ∼8 hours awake, attentional failure rate was low, irrespective of the week. During the following wake hours, attentional failure rate increased steadily but at a faster rate in weeks 2 and 3 compared to week 1. The effects of acute and chronic sleep loss on attentional failure rate were magnified during the biological night compared to the biological day. CONCLUSIONS: A single extended sleep episode can only temporarily reverse attentional impairment associated with chronic sleep loss. Multiplicative effects of acute and chronic sleep loss-further amplified during the biological night-substantiate the interaction of 2 homeostatic response mechanisms and caution against underestimating their disproportionate combined impact on performance, health, and safety.

Effects of total sleep deprivation on performance in a manual spacecraft docking task.

Sleep deprivation and circadian rhythm disruptions are highly prevalent in shift workers, and also among astronauts. Resulting sleepiness can reduce cognitive performance, lead to catastrophic occupational events, and jeopardize space missions. We investigated whether 24 hours of total sleep deprivation would affect performance not only in the Psychomotor Vigilance Task (PVT), but also in a complex operational task, i.e. simulated manual spacecraft docking. Sixty-two healthy participants completed the manual docking simulation 6df and the PVT once after a night of total sleep deprivation and once after eight hours of scheduled sleep in a counterbalanced order. We assessed the impact of sleep deprivation on docking as well as PVT performance and investigated if sustained attention is an essential component of operational performance after sleep loss. The results showed that docking accuracy decreased significantly after sleep deprivation in comparison to the control condition, but only at difficult task levels. PVT performance deteriorated under sleep deprivation. Participants with larger impairments in PVT response speed after sleep deprivation also showed larger impairments in docking accuracy. In conclusion, sleep deprivation led to impaired 6df performance, which was partly explained by impairments in sustained attention. Elevated motivation levels due to the novelty and attractiveness of the task may have helped participants to compensate for the effects of sleepiness at easier task levels. Continued testing of manual docking skills could be a useful tool both to detect sleep loss-related impairments and assess astronauts' readiness for duty during long-duration missions.

Influence of circadian phase and extended wakefulness on glucose levels during forced desynchrony.

OBJECTIVES: Circadian misalignment and sleep deprivation often occur in tandem, and both negatively impact glucose homeostasis and metabolic health. The present study employed a forced desynchrony protocol to examine the influence of extended wakefulness and circadian misalignment on hourly glucose levels. METHODS: Nine healthy adults (4F/5M; 26 ± 4years) completed a 31-day in-laboratory protocol. After three 24 hour baseline days with 8 hours scheduled sleep opportunities, participants were scheduled to 14 consecutive 42.85 hour sleep-wake cycles, with 28.57 hours extended wakefulness and 14.28 hours sleep opportunities each cycle. Blood was sampled hourly across the forced desynchrony and over 600 plasma samples per participant were analyzed for glucose levels. RESULTS: Both hours into the 42.85 hours forced desynchrony day and circadian phase modulated glucose levels (p < .0001). Glucose peaked after each meal during scheduled wakefulness and decreased during scheduled sleep/fasting. Glucose levels were, on average, lowest during the biological daytime and rose throughout the biological night, peaking in the biological morning. When analyzed separately for scheduled sleep vs. wakefulness, the peak timing of the circadian rhythm in glucose was later during sleep (p < .05). Glucose area under the curve levels increased rapidly from the beginning of the forced desynchrony protocol and were highest on the second forced desynchrony day (p < .01), returning towards forced desynchrony day 1 levels thereafter. CONCLUSIONS: These findings have important implications for understanding factors contributing to altered glucose metabolism during sleep loss and circadian misalignment, and for potential physiological adaptation of metabolism in healthy adults, who are increasingly exposed to such conditions in our society.

Repeated caffeine intake suppresses cerebral grey matter responses to chronic sleep restriction in an A1 adenosine receptor-dependent manner: a double-blind randomized controlled study with PET-MRI.

Evidence has shown that both sleep loss and daily caffeine intake can induce changes in grey matter (GM). Caffeine is frequently used to combat sleepiness and impaired performance caused by insufficient sleep. It is unclear (1) whether daily use of caffeine could prevent or exacerbate the GM alterations induced by 5-day sleep restriction (i.e. chronic sleep restriction, CSR), and (2) whether the potential impact on GM plasticity depends on individual differences in the availability of adenosine receptors, which are involved in mediating effects of caffeine on sleep and waking function. Thirty-six healthy adults participated in this double-blind, randomized, controlled study (age = 28.9 ± 5.2 y/; F:M = 15:21; habitual level of caffeine intake < 450 mg; 29 homozygous C/C allele carriers of rs5751876 of ADORA2A, an A2A adenosine receptor gene variant). Each participant underwent a 9-day laboratory visit consisting of one adaptation day, 2 baseline days (BL), 5-day sleep restriction (5 h time-in-bed), and a recovery day (REC) after an 8-h sleep opportunity. Nineteen participants received 300 mg caffeine in coffee through the 5 days of CSR (CAFF group), while 17 matched participants received decaffeinated coffee (DECAF group). We examined GM changes on the 2nd BL Day, 5th CSR Day, and REC Day using magnetic resonance imaging and voxel-based morphometry. Moreover, we used positron emission tomography with [18F]-CPFPX to quantify the baseline availability of A1 adenosine receptors (A1R) and its relation to the GM plasticity. The results from the voxel-wise multimodal whole-brain analysis on the Jacobian-modulated T1-weighted images controlled for variances of cerebral blood flow indicated a significant interaction effect between caffeine and CSR in four brain regions: (a) right temporal-occipital region, (b) right dorsomedial prefrontal cortex (DmPFC), (c) left dorsolateral prefrontal cortex (DLPFC), and (d) right thalamus. The post-hoc analyses on the signal intensity of these GM clusters indicated that, compared to BL, GM on the CSR day was increased in the DECAF group in all clusters  but decreased in the thalamus, DmPFC, and DLPFC in the CAFF group. Furthermore, lower baseline subcortical A1R availability predicted a larger GM reduction in the CAFF group after CSR of all brain regions except for the thalamus. In conclusion, our data suggest an adaptive GM upregulation after 5-day CSR, while concomitant use of caffeine instead leads to a GM reduction. The lack of consistent association with individual A1R availability may suggest that CSR and caffeine affect thalamic GM plasticity predominantly by a different mechanism. Future studies on the role of adenosine A2A receptors in CSR-induced GM plasticity are warranted.

Associations between resting state brain activity and A1 adenosine receptor availability in the healthy brain: Effects of acute sleep deprivation.

Introduction: Previous resting-state fMRI (Rs-fMRI) and positron emission tomography (PET) studies have shown that sleep deprivation (SD) affects both spontaneous brain activity and A1 adenosine receptor (A1AR) availability. Nevertheless, the hypothesis that the neuromodulatory adenosinergic system acts as regulator of the individual neuronal activity remains unexplored. Methods: Therefore, fourteen young men underwent Rs-fMRI, A1AR PET scans, and neuropsychological tests after 52 h of SD and after 14 h of recovery sleep. Results: Our findings suggested higher oscillations or regional homogeneity in multiple temporal and visual cortices, whereas decreased oscillations in cerebellum after sleep loss. At the same time, we found that connectivity strengths increased in sensorimotor areas and decreased in subcortical areas and cerebellum. Discussion: Moreover, negative correlations between A1AR availability and rs-fMRI metrics of BOLD activity in the left superior/middle temporal gyrus and left postcentral gyrus of the human brain provide new insights into the molecular basis of neuronal responses induced by high homeostatic sleep pressure.

Oral fructose intake does not improve exercise, visual, or cognitive performance during acute normobaric hypoxia in healthy humans.

Introduction: The ability to metabolize fructose to bypass the glucose pathway in near-anaerobic conditions appears to contribute to the extreme hypoxia tolerance of the naked-mole rats. Therefore, we hypothesized that exogenous fructose could improve endurance capacity and cognitive performance in humans exposed to hypoxia. Methods: In a randomized, double-blind, crossover study, 26 healthy adults (9 women, 17 men; 28.8 ± 8.1 (SD) years) ingested 75 g fructose, 82.5 g glucose, or placebo during acute hypoxia exposure (13% oxygen in a normobaric hypoxia chamber, corresponding to oxygen partial pressure at altitude of ~3,800 m) on separate days. We measured exercise duration, heart rate, SpO2, blood gasses, and perceived exertion during a 30-min incremental load test followed by Farnsworth-Munsell 100 Hue (FM-100) color vision testing and the unstable tracking task (UTT) to probe eye-hand coordination performance. Results: Exercise duration in hypoxia was 21.13 ± 0.29 (SEM) min on fructose, 21.35 ± 0.29 min on glucose, and 21.35 ± 0.29 min on placebo (p = 0.86). Heart rate responses and perceived exertion did not differ between treatments. Total error score (TES) during the FM-100 was 47.1 ± 8.0 on fructose, 45.6 ± 7.6 on glucose and 53.3 ± 9.6 on placebo (p = 0.35) and root mean square error (RMSE) during the UTT was 15.1 ± 1.0, 15.1 ± 1.0 and 15.3 ± 0.9 (p = 0.87). Discussion: We conclude that oral fructose intake in non-acclimatized healthy humans does not acutely improve exercise performance and cognitive performance during moderate hypoxia. Thus, hypoxia tolerance in naked mole-rats resulting from oxygen-conserving fructose utilization, cannot be easily reproduced in humans.

Sleep and anxiety: From mechanisms to interventions.

Anxiety is the most common mental health problem worldwide. Epidemiological studies show that sleep disturbances, particularly insomnia, affect ∼50% of individuals with anxiety, and that insufficient sleep can instigate or further exacerbate it. This review outlines brain mechanisms underlying sleep and anxiety, by addressing recent human functional/structural imaging studies on brain networks underlying the anxiogenic impact of sleep loss, and the beneficial effect of sleep on these brain networks. We discuss recent developments from human molecular imaging studies that highlight the role of specific brain neurotransmitter mechanisms, such as the adenosinergic receptor system, on anxiety, arousal, and sleep. This review further discusses frontline sleep interventions aimed at enhancing sleep in individuals experiencing anxiety, such as nonbenzodiazepines/antidepressants, lifestyle and sleep interventions and cognitive behavioral therapy for insomnia. Notwithstanding therapeutic success, up to ∼30% of individuals with anxiety can be nonresponsive to frontline treatments. Thus, we address novel non-invasive brain stimulation techniques that can enhance electroencephalographic slow waves, and might help alleviate sleep and anxiety symptoms. Collectively, these findings contribute to an emerging biological framework that elucidates the interrelationship between sleep and anxiety, and highlight the prospect of slow wave sleep as a potential therapeutic target for reducing anxiety.