Abstract Introduction When switching between daytime and nighttime flying or during transmeridian trips, flight crew may encounter layovers that are ~24h in duration. Managing sleep during these layovers is challenging: Sleeping early helps to recover from the prior duty period, while sleeping late helps to prepare for the next one, and circadian rhythmicity constrains when sleep is possible. We used computer simulations based on the two-process model (TPM) of sleep/wake regulation to explore optimal 24h layover sleep strategies. Methods We simulated all possible sleep schedules during 24h layovers with 4h–8h total sleep opportunity, scheduled in 1h increments as consolidated sleep opportunity or split between two sleep opportunities of ≥2h duration and ≥2h apart. For each simulated sleep schedule, and for all possible layover start times in 1h steps, we tracked the homeostatic and circadian processes of the TPM across the 24h layover and a subsequent 12h duty period. Initial homeostatic sleep pressure at the layover start was assumed to be 0.62 or 0.85 (moderate or considerable prior wakefulness). Evaluated at 30min resolution, the model marked when sleep would occur during the scheduled sleep opportunities, based on homeostatic pressure exceeding the lower TPM circadian threshold (i.e., sleep was biologically plausible). The model also flagged when, outside of scheduled sleep opportunities, homeostatic pressure exceeded the upper circadian threshold (i.e., effort required to stay awake). Additionally, we calculated the peak level of sleepiness (homeostatic sleep pressure minus circadian wake pressure) during the subsequent 12h duty period. Results Among all simulated 24h layover sleep schedules the most (compared to least) effective ones yielded ~25%–50% reductions in peak sleepiness during the subsequent 12h duty period. For ≥6h total sleep opportunities, irrespective of 24h layover start time, optimal sleep scheduling involved split sleep with one sleep period near the start and another near the end of the layover. For ≥7h total sleep opportunities, regardless of initial homeostatic state (0.62, 0.85), none of the optimal sleep schedules were flagged as requiring effort to stay awake. Conclusion Biomathematical simulations for scheduling of sleep during 24h layovers suggest that optimal planning entails ≥7h, split sleep opportunities. Support (if any) Federal Express Corporation

Abstract Introduction People with idiopathic hypersomnia often experience sleep inertia, characterized by profound difficulty waking up with grogginess, disorientation, and cognitive impairment immediately after awakening. This post-hoc analysis of the DUET study (NCT05875974) evaluated objective and subjective sleep inertia in participants with idiopathic hypersomnia taking low-sodium oxybate (LXB; Xywav®) stratified by patient-reported ideal nighttime sleep duration (with [>9h] and without [≤9h] long sleep need [LSN]), based on Idiopathic Hypersomnia Severity Scale (IHSS) item 1. Methods DUET was a phase 4, prospective, open-label study of LXB with baseline (BL), titration/optimization, stable-dose, and end-of-treatment (EOT) periods. Exploratory outcomes included Psychomotor Vigilance Test (PVT; objective performance impairment) and Karolinska Sleepiness Scale (KSS; subjective sleepiness), administered BL and EOT, in the morning after overnight polysomnogram. The 10-minute PVT was completed at 10, 40, and 90 minutes after awakening. The KSS, a single-item, 9-point scale, was completed upon awakening and immediately before/after PVT assessments. Separate nonlinear, mixed-effects regression models were applied to PVT lapses and KSS ratings to estimate objective and subjective sleep inertia magnitudes, respectively, in LSN subgroups, along with sleep inertia dissipation time constants for the overall cohort. Treatment-emergent adverse events (TEAEs) were assessed. Results Of 46 enrolled participants with idiopathic hypersomnia, 45 had BL IHSS data; 24 reported LSN and 21 reported no LSN. Most (with/without LSN) were female (100.0%/61.9%) and White (91.7%/76.2%); 20/24 and 19/21 completed the study. Based on PVT lapses, objective sleep inertia ±SE (with/without LSN) at BL was 17.0±4.2/4.2±2.8, and at EOT was 0.0±na/2.0±0.9 (BL-to-EOT changes [95% CI]: −17.0 [−25.5, −8.5] and −2.2 [−6.9, 2.5]). Based on KSS, subjective sleep inertia ±SE (with/without LSN) at BL was 6.5±0.3/5.1±0.5, and at EOT was 0.81±0.5/1.5±0.6 (BL-to-EOT changes [95% CI]: −5.7 [−6.7, −4.7] and −3.5 [−4.5, −2.6]). Sleep inertia dissipation time constants ±SE were 2.7±1.1h (PVT) and 13.9±3.8h (KSS). TEAEs were consistent with the known LXB safety profile. Conclusion Participants with idiopathic hypersomnia experienced subjective and objective sleep inertia at BL, with prolonged dissipation after awakening. Objective BL sleep inertia was particularly severe in participants with LSN (>9h). After LXB treatment, notable improvements in objective and subjective sleep inertia were observed for both subgroups. Support (if any) Jazz Pharmaceuticals

Alzheimers disease (AD) is characterized by the mis-aggregation of amyloid beta and tau, which is proposed to be driven by impaired amyloid beta and tau clearance. While sleep-active glymphatic transport contributes to the clearance of amyloid beta and tau in humans, studies have yet to demonstrate that it is possible to enhance glymphatic transport in humans and that augmenting glymphatic transport improves the clearance of amyloid beta and tau from the human brain. In two cross-over clinical trials in healthy older adults, we demonstrated that a fixed-dose combination therapy of intravenous dexmedetomidine (0.7 mcg/kg/h) and 10 mg oral midodrine (ACX-02), that suppressed central noradrenergic tone while maintaining systemic arterial pressure, increased EEG slow waves, enhanced cerebrovascular pulsatility, and reduced parenchymal resistance to perivascular fluid flow, that have shown to be key determinants of glymphatic transport. Dynamic shifts in plasma mass balance indices of clearance within the brain demonstrated that pharmacological enhancement of glymphatic transport increased amyloid beta and tau clearance by approximately 9% - 10% during a single 4h 15min sleep opportunity. Bayesian mediation analysis demonstrated that increasing EEG slow waves and declining parenchymal resistance were key mediators, and cerebrovascular compliance was a moderator, of the effect of ACX-02 on plasma AD biomarker dynamics. These findings demonstrate that pharmacologic enhancement of glymphatic transport increased brain-to-blood clearance of amyloid beta and tau in human participants. This suggests that enhancement of amyloid beta and tau clearance may serve as a complementary approach to existing disease-modifying therapies, and as a therapeutic approach in AD and AD-related proteinopathies. ### Competing Interest Statement The authors PD, LG, AC, JJI declare the existence of financial and incentive stock options competing interests. BPL is an advisor to Applied Cognition and declares the existence of incentive stock option competing interests. KY is an advisor to C2N Diagnostics and receives stock options. The remaining authors declare no competing interests. ### Clinical Trial Clinical Trial ID: [NCT07432997][1] ### Funding Statement This work was funded by Applied Cognition. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Western Institutional Review Board (IRB No. 20232285) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available with Institutional Review Board approval and a Data Use Agreement. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT07432997&atom=%2Fmedrxiv%2Fearly%2F2026%2F03%2F12%2F2026.03.10.26348048.atom

Abstract Introduction Sleep inertia (characterized by profound difficulty waking up with grogginess, disorientation, and cognitive impairment immediately after awakening) is a core idiopathic hypersomnia symptom and may also be experienced by individuals with narcolepsy. Sleep inertia in individuals with narcolepsy is not well studied. This post-hoc analysis of the DUET study (NCT05875974) evaluated sleep inertia in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) subgroups of the DUET narcolepsy cohort. Methods DUET was a phase 4, prospective, open-label study with baseline (BL), titration/optimization, stable-dose, and end-of-treatment (EOT) periods. Exploratory outcomes included Psychomotor Vigilance Test (PVT; objective performance impairment) and Karolinska Sleepiness Scale (KSS; subjective sleepiness); both administered at BL and EOT, in the morning after overnight polysomnogram. The 10-minute PVT was completed at 10, 40, and 90 minutes after awakening. The KSS, a single-item, 9-point scale, was completed upon awakening and immediately before and after the PVT assessments. Separate nonlinear, mixed-effects regression models were applied to PVT lapses and KSS ratings to estimate objective and subjective sleep inertia magnitudes, respectively, for NT1 and NT2, along with sleep inertia dissipation time constants for the overall cohort. Treatment-emergent adverse events (TEAEs) were assessed. Results Of 55 enrolled participants with narcolepsy, 26 and 29 had NT1 and NT2, respectively. Most (NT1/NT2) were female (73.1%/72.4%) and White (73.1%/86.2%); 16/26 and 18/29 completed the study. Based on PVT lapses, objective sleep inertia ±SE (NT1/NT2) at BL was 33.1±6.2/14.9±3.2, and at EOT was 8.3±1.7/3.2±1.1 (BL-to-EOT changes [95% CI]: −24.8 [−35.5, −14.1] and −11.8 [−17.4, −6.1]). Based on KSS ratings, subjective sleep inertia ±SE (NT1/NT2) at BL was 1.1±0.6/1.1±0.5, and at EOT was 0.8±0.5/1.3±0.5 (BL-to-EOT changes [95% CI]: −0.3 [−1.9, 1.2] and 0.2 [−1.3, 1.6]). Sleep inertia dissipation time constants ±SE were 1.6±0.3h (PVT) and 0.4±0.1h (KSS) for the overall cohort. TEAEs were consistent with the known LXB safety profile. Conclusion Participants with narcolepsy, especially NT1, demonstrated objective sleep inertia at BL. Participants with NT1 or NT2 showed substantial improvements in objective sleep inertia with LXB treatment. Support (if any) Jazz Pharmaceuticals

Automation has pushed industries to operate around the clock and increased the need for extended and nighttime working times. Here we explore the effects of fatigue from sleep loss in highly automated operational settings, and how technology shapes the way these effects are managed. The influx of technology and automation into the modern workplace has shifted the emphasis of human work activity toward systems monitoring and intervening tasks. Such tasks place a high burden on sustained attention and attentional control, and recent findings have shown that these aspects of cognition are highly sensitive to fatigue due to sleep loss. Technological developments in fatigue detection and management can be brought to bear on addressing the associated risks. Automation has made workplaces safer and more productive, but by helping to extend industrial activity to all hours of the day, it has also created new, fatigue-related risks to safety and productivity. Research is needed to better understand the functioning of fatigued individuals in highly automated environments and the effective mitigation of fatigue-related risk.

Chronically restricted nighttime sleep propagates an accumulation of objective performance deficits over days, but subjective sleepiness does not equivalently reflect this build-up of impairment. Here we studied the dynamics of subjective sleepiness over days with restricted sleep placed in the late morning or afternoon. N=72 healthy young adults (ages 21-45y, 39% female) completed a 14-day in-laboratory study. After an 8h nighttime adaptation sleep opportunity (23:30–07:30) there was a baseline day with an 8h shifted sleep opportunity ending in late A) morning (11:30) or B) afternoon (19:30). Participants were then randomized to 9 consecutive days of restricted sleep with 4h, 6h, or 8h TIB ending in late A) morning (11:30; n=19, 8, 8, respectively), or B) afternoon (19:30 n=13, 17, 7, respectively). Participants rated their sleepiness on the Karolinska Sleepiness Scale (KSS) at ~2h intervals during scheduled wakefulness. Daily averages for sleepiness rated 2-14h after scheduled awakening, expressed relative to the shifted baseline, were analyzed with nonlinear mixed-effects regression to investigate the temporal dynamics of subjective sleepiness. In the late afternoon conditions, KSS sleepiness displayed a significant sleep dose-dependence (F=3.44, p=0.038). There was no significant change over the 9 days of sleep restriction for either the 4h or 6h sleep doses, but the 8h dose showed a modest decrease in KSS sleepiness over days (t=-3.11, p=0.003). In the late morning conditions, KSS sleepiness exhibited no sleep dose-dependence (F=0.62, p=0.54), and there were no significant changes over the 9 days of sleep restriction (t=1.42, p=0.16). The dynamics of participants’ subjective sleepiness across days of late afternoon sleep restriction were incongruent with their sleep dose-response accumulation of objective performance impairment (see companion abstract by Banks et al.). Rather, it seemed that subjective sleepiness stabilized in participants randomized to 6h or 4h restricted sleep opportunities, with some apparent adaptation to the shifted sleep timing over days for those randomized to the 8h sleep opportunities. However, across days of late morning sleep restriction, the afternoon circadian promotion of wakefulness appeared to mitigate participants’ subjective sleepiness for at least 14h of wakefulness daily, as was also observed for their objective performance impairment. NIH R01-NR04281, M01-RR00040

Maternal sleep disruption is common throughout the first postpartum year, and particularly severe in the first postpartum week. As nearly 75% of all pregnancy-related maternal deaths occur between postpartum days 1 and 7, maternal sleep disruption after birth could be a risk factor for maternal morbidity and mortality. Here, in a sample of first-time mothers, we quantified objectively measured sleep during the first 7 postpartum days. N=41 first-time mothers (ages 26–43y) recorded their wrist activity (Fitbit) continuously across postpartum days 1-7. Sleep data were analyzed in 5min bins, using ≥10min consecutive sleep and wake as criteria for onset and offset of sleep periods, respectively. Sleep duration (including naps) and longest stretch of sleep (LSS) were calculated for each 24h day. Off-wrist detection was based on absence of heart rate data and controlled for in analyses. The incidence of acute total sleep deprivation (>24h without sleep) was 20% (n=8) on day 1, 20% (n=8) on day 2, and 10% (n=4) on days 3-7. Total 24h sleep duration ranged from a low of 2.7±2.2h (mean±SD) on day 1 to a high of 5.0±2.0h on day 7. LSS ranged from a low of 1.7±1.4h on day 1 to a high of 2.9±1.2h on day 7. These results show that acute total sleep deprivation is common in new mothers after giving birth. The results also show severe chronic sleep restriction during the first postpartum week, with the average first-time mother in our sample obtaining no more than 5h total sleep duration per 24h and consolidated sleep periods shorter than 3h – much less even during the first few postpartum days. Our findings provide objective evidence of considerable maternal sleep disruption, making sleep disruption a plausible contributor to maternal health risks in the first postpartum week. Limitations of the study include that the sample was predominantly white, relatively affluent, and generally in good health. The sleep data nonetheless suggest that studies should investigate whether there is a causal relationship between maternal sleep disruption and health risks, and whether interventions to protect maternal sleep during the first postpartum week may improve health outcomes. trackthatsleep LLC

To assess whether solriamfetol, a dopamine-norepinephrine reuptake inhibitor (DNRI) approved to improve wakefulness in adults with obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS), could improve memory performance, preclinically, and cognition in EDS from OSA, clinically.

Acute total sleep deprivation (TSD) is common due to extended work hours or other time demands. In controlled laboratory settings, individuals exposed to TSD display highly reproduceable profiles of neurobehavioral impairment. In real-world settings, however, TSD is often combined with substance intake, including alcohol and cannabis. In this pilot study, we investigated the effect of substance intake on the neurobehavioral response to TSD. Six healthy individuals (ages 23-37y, all male) completed two 24h in-laboratory study visits separated by ≥1 week. During each visit, they were kept awake from 15:00 until 06:00 the next day, and they completed a 10min PVT every 2-3h. This was followed by an 8h recovery sleep opportunity. For the second visit, participants were randomized – three per group – to receive oral administration of cannabis at 22:30 (10mg) or alcohol at 23:30 (peak blood alcohol concentration of 0.043±0.006% at 00:13, decaying to 0.005±0.007% by 03:55). PVT mean RT, number of lapses (RT>500ms) and false starts were analyzed using mixed-effects regression. As expected, PVT performance deteriorated through the second half of the extended waking period (after midnight), with slower mean RT, more lapses, and more false starts (F>3.6, P< 0.002). Alcohol increased mean RT (F=4.9, P=0.002) and lapses (F=7.7, P< 0.001), but did not significantly affect false starts (F=1.0, P=0.41). Cannabis did not significantly affect mean RT (F=0.9, P=0.46), lapses (F=1.1, P=0.37), or false starts (F=0.8, P=0.56) during TSD. Alcohol exacerbated neurobehavioral impairment during TSD, even at blood alcohol levels below the legal limit of most countries and states, reaching statistical significance despite our small sample size. Cannabis at the dose provided did not significantly further degrade PVT performance during TSD. Importantly, no attempt was made to make the alcohol and cannabis doses equipotent; therefore, these results should not be interpreted as evidence of their relative effect sizes or safety profiles. Yet, our findings provide preliminary evidence suggesting that commonly used drugs such as alcohol may amplify neurobehavioral impairment from sleep loss, which may have critical implications for automobile driving and other safety-sensitive activities. National Safety Council

Maternal sleep is disrupted during the postpartum period, but the nature and severity of sleep disruption has not been adequately documented. Studies of sleep duration have reported only modest sleep loss beyond the first week after giving birth, leaving first-time mothers poorly prepared for what kind of sleep disruption to expect. Using sleep data from first-time mothers’ personal wearables (Fitbit), we examined sleep duration and the longest stretch of sleep (LSS) – a sleep consolidation metric commonly used for infant sleep – to quantify maternal sleep during the first 13 postpartum weeks. N=41 first-time mothers (ages 26–43y) provided their sleep/wake wearable data from a full year before childbirth to the end of the first postpartum year. Sleep data were analyzed in 5min bins, using ≥10min consecutive sleep and wake as criteria for onset and offset of sleep periods, respectively. Off-wrist detection was based on absence of heart rate data. Daily sleep duration and LSS were calculated for each 24-hour day and compared between the first 13 postpartum weeks and the equivalent days of the prior year (preconception baseline). During postpartum week 1, daily sleep duration was 4.4±0.2h (mean±SEM) compared to 7.8±0.2h at preconception baseline. Daily LSS was 2.2±0.2h versus 5.6±0.2h preconception. 31.7% of participants went >24h without sleep. Across postpartum weeks 2-7, daily sleep duration increased to 6.7±0.1h versus 7.7±0.1h preconception. However, daily LSS stayed low at 3.2±0.1h versus 5.5±0.1h preconception. Across postpartum weeks 8-13, daily sleep duration was 7.3±0.1h versus 7.9±0.1h preconception. Yet, daily LSS was still reduced at 4.1±0.1h versus 5.6±0.1h preconception. All differences were significant (F>29.8, P< 0.001). Sleep duration was greatly reduced during the first postpartum week, but gradually returned to near baseline levels thereafter. However, sleep consolidation, as captured by LSS, stayed considerably below preconception baseline throughout the first 13 postpartum weeks. This suggests that in postpartum weeks 2-13, sleep discontinuity – more so than sleep loss – contributed most prominently to first-time mothers’ sleep disruption. Sleep discontinuity may be a risk factor and intervention target for postpartum depression and other postpartum-related health issues. trackthatsleep LLC

Striatal dopaminergic and adenosinergic signaling mechanisms are believed to mediate neurobehavioral impairment during total sleep deprivation (TSD). A variable number tandem-repeat polymorphism in the dopamine transporter gene (DAT1) modulates striatal dopamine and trait vulnerability to TSD. However, trait vulnerability to TSD is task-dependent. We conducted a pharmacogenetic study to investigate the role of striatal dopaminergic circuits in mediating TSD-induced impairment on distinct neurobehavioral tasks. N=73 healthy adults (ages 25.2±5.2y; 39 males) completed a double-blind, in-laboratory TSD study. After a 10h sleep opportunity, subjects underwent 38h TSD and were randomly assigned to a drug condition. At 4h intervals from 17h to 29h awake (01:00, 05:00, 09:00, and 13:00), they received caffeine (200mg/dose; n=26), modafinil (alternating 200mg and 0mg doses; n=25), or placebo (n=22). At ~2h intervals throughout TSD, a 10min Psychomotor Vigilance Test (PVT), 4min Digit Symbol Substitution Task (DSST), and Karolinska Sleepiness Scale (KSS) were administered to measure vigilant attention, associative learning, and subjective sleepiness, respectively. PVT log-transformed signal-to-noise ratio (LSNR), DSST number correct, and KSS ratings were expressed relative to well-rested baseline (11:30–20:00 average) and analyzed using mixed-effects regression. There were 44 DAT1 10-repeat (10R) allele homozygotes and 29 DAT1 9-repeat (9R) allele carriers, with 16/16/12 (10R/10R) and 10/9/10 (9R) subjects in the caffeine/modafinil/placebo conditions. DAT1 genotype modulated PVT performance in the placebo (F[1,67]=5.92, p=0.018) and caffeine (F[1,67]=5.26, p=0.025) conditions, whereas it modulated DSST performance in the modafinil (F[1,67]=13.16, p< 0.001) and placebo (F[1,67]=5.71, p=0.020) conditions, with the 10R homozygotes exhibiting less impairment. DAT1 genotype also modulated KSS ratings in the caffeine condition (F[1,67]=5.53, p=0.024), but the 10R homozygotes reported greater sleepiness. DAT1 genotype modulated neurobehavioral impairment during TSD in a task-dependent and drug-dependent manner, indicating distinct underlying mechanisms. Our results corroborate earlier findings that TSD-induced deficits in vigilant attention are dissociable from those in associative learning, and both are dissociable from subjective sleepiness. The observed genotype by drug interaction corroborates modafinil’s purported dopaminergic mechanism of action. Our findings are consistent with a role for integrated dopaminergic and adenosinergic signaling mechanisms of the striatal indirect pathway in modulating some, but not all, aspects of sleep-deprived neurobehavioral functioning. USAMRDC W81XWH-18-1-0100

Postpartum maternal sleep is disrupted, even after stabilizing following the first three months. Evidence suggests that breastfeeding women wake more often during the night than those who use infant formula, while sleep duration is similar. Here we investigated the effects of breastmilk versus formula feeding on maternal sleep across postpartum weeks 14-52. N=41 first-time mothers (26-43y) recorded their sleep (Fitbit) and reported infant milk type – breastmilk or formula – with 16 participants also logging daily infant feeding events (mobile app). Daily sleep duration and continuity (LSS: longest stretch of sleep) were assessed by 24h day. Effects of milk type were analyzed with mixed-effects ANCOVA, controlling for general trends across days. Mean daily sleep duration was 7.4h throughout postpartum weeks 14-52, whereas LSS increased from 4.3h to 5.3h. In week 14, 64.7% of participants fed breastmilk, 17.1% formula, and 18.2% mixed. By week 52, 47.2% fed breastmilk, 43.5% formula, and 9.3% mixed. Milk type did not affect sleep duration (F=2.6, P=0.11), but those feeding breastmilk had 0.4h shorter LSS than those feeding formula or mixed (F=10.2, P=0.001). Among those logging feeding events, milk type did not affect sleep duration (F=0.8, P=0.38), but LSS was shorter by 6.2min per feeding event for breastmilk compared to formula (F=12.0, P< 0.001). There were no significant relationships with breastmilk pumping, breastfeeding versus breastmilk bottle feeding, infant weight gain, or infant sleep training. On average there were 9.1 daily feeding events for exclusive breastmilk feeding, compared to 7.3 for formula or mixed (F=10.9, P=0.001). In this predominantly white and relatively affluent sample, maternal sleep duration in postpartum weeks 14-52 did not vary by infant milk type. However, participants who fed their babies formula had fewer daily feeding events and greater sleep continuity than participants who exclusively fed their babies breastmilk. As there was no effect of breastfeeding versus breastmilk bottle feeding, use of infant formula per se may have led to increased maternal sleep continuity. Whether a difference in infant sleep continuity is involved remains to be investigated. Regardless, current recommendations of exclusive breastmilk feeding may come at a cost to maternal sleep. trackthatsleep LLC

Chronic nighttime sleep restriction leads to the build-up of neurobehavioral impairment across days. Although it is known that the circadian timing of sleep mediates the effects of sleep loss, it is not known how the timing of restricted sleep influences the accumulation of neurobehavioral impairment over days. Here we investigated lapses on the psychomotor vigilance test (PVT) across days with restricted sleep placed in the late morning or late afternoon. N=72 healthy young adults (ages 21-45y, 39% female) completed a 14-day in-laboratory study. After an 8h nighttime adaptation sleep opportunity (23:30–07:30) there was a baseline day with an 8h shifted sleep opportunity ending in late A) morning (11:30) or B) afternoon (19:30). Subjects were then randomized to 9 consecutive days of sleep restricted to 4h, 6h, or 8h time-in-bed (TIB) for late A) morning (11:30; n=19, 8, 8, respectively), or B) afternoon (19:30; n=13, 17, 7, respectively). Subjects were tested on a 10-minute PVT every ~2h during scheduled wakefulness. Daily averages for PVT lapses (RTs>500ms) observed 2-14h after scheduled awakening, expressed relative to average PVT lapses on theshifted baseline day, were analyzed with nonlinear mixed-effects regression to investigate differences in the build-up of neurobehavioral impairment between shifted sleep restriction doses. In the afternoon sleep conditions, PVT lapses showed a significant sleep dose-response effect (F=6.22, p=0.003), with the fastest accrual of impairment across days in the 4h condition (t=5.12, p< 0.001) and near-negligible impairment build-up in the 8h condition (t=1.00, p=0.32). However, in the morning sleep conditions, PVT lapses showed no sleep dose-response effect (F=0.01, p=0.99) with modest impairment growth across days overall (t=2.06, p=0.043) at just 43.7% the average rate observed in the afternoon sleep conditions. In this sample of young adults, placing 6h and 4h daily sleep opportunities in the late morning appeared to provide resilience against the accumulation of neurobehavioral impairment from sustained sleep restriction. Our results suggest that afternoon circadian promotion of wakefulness can sustain objective neurobehavioral functioning for at least 14h of wakefulness daily across multiple days of sleep restriction. NIH R01-NR04281, M01-RR00040

Recent studies employing a laboratory study design with randomization to simulated night shift (NS) or day shift (DS) followed by a constant routine protocol exposed widespread NS-induced disruptions in endogenous biomolecular circadian rhythms. To investigate whether this generalizes to long-term NS workers in real-world shift schedules, we modified the design to a field/laboratory study combining participants’ own real-world work shifts with a schedule-adapted laboratory constant routine. As part of an ongoing study, 15 long-term DS workers and 7 long-term NS workers (ages 27-55y; 12f) participated in the combined field/laboratory study. After completing ≥3 consecutive DS or NS shifts, participants slept at home and then reported to the laboratory at 08:00 (DS) or 20:00 (NS) as if beginning another shift. After 2h laboratory acclimation they underwent a strictly controlled 24h constant routine with continuous wakefulness, fixed posture, and hourly isocaloric snacks. They completed the psychomotor vigilance test (PVT) and Karolinska Sleepiness Scale (KSS) every 3h. The two-process model was fitted to PVT lapses (RTs>500ms) and KSS sleepiness to compare the homeostatic and circadian processes between DS and NS workers. PVT lapses and KSS sleepiness increased steadily across the 24h constant routine in the DS workers, while peaking after both 14h and 24h in the NS workers as predicted by the two-process model (χ2=270.2, p< 0.001). There was no difference in initial sleep homeostatic state between DS and NS workers (F=0.28, p=0.60), but the circadian process was delayed by 0.9±0.3h (mean±SE) in the NS workers (F=13.74, p=0.001). In this combined field/laboratory study, the homeostatic and circadian processes produced expected neurobehavioral dynamics, even though the 24h constant routine started 12h later in the NS workers in accordance with their shifted prior work schedules. DS and NS workers did not differ in initial sleep homeostatic state, but there was a small delay in the endogenous circadian phase of the NS workers, as commonly observed in real-world shift operations. While awaiting confirmation with circulating melatonin, our results support the viability of this novel study design and its use for investigating the impact of real-world NS on biomolecular circadian rhythms. CARE Fund FY22-POP-02; HSSA; WSU ESFCOM

Study Objectives:There are large individual differences in the homeostatic response to sleep deprivation, as reflected in slow wave sleep (SWS) and electroencephalogram (EEG) spectral power, which have largely been left unexplained. Recent evidence suggests the possible involvement of the activity-regulated cytoskeleton-associated protein (ARC) gene. Here we assessed the effects of the "c.*742 + 58C > T non-coding single nucleotide polymorphism" of the human ARC gene (rs35900184) on sleep-physiological and waking-neurobehavioral responses to total sleep deprivation (TSD). Methods:N = 50 healthy, young adults participated in a 4-day/3-night in-laboratory study with a 38-h TSD period, flanked by 10-h baseline and recovery sleep opportunities. Sleep was recorded polysomnographically and the EEG of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep was subjected to spectral analysis. Waking neurobehavioral functioning was measured with the psychomotor vigilance test (PVT) and the Karolinska Sleepiness Scale (KSS). Results:ARC C/C homozygotes, compared to T allele carriers, showed a greater SWS rebound during recovery sleep after TSD relative to baseline. ARC T/T homozygotes showed increased EEG spectral power in the NREM theta and alpha bands and in the REM delta, theta, alpha, and beta bands, but there was no significant genotype difference in the NREM delta power response to TSD. There were also no significant genotype differences in the impact of TSD on PVT performance and KSS sleepiness. Conclusions:Individual differences in the sleep physiological rebound after TSD were influenced by ARC genotype. However, our findings were only partially consistent with ARC mediating the sleep homeostatic response to sleep deprivation. This article is part of the Genetic and Other Molecular Underpinnings of Sleep, Sleep Disorders, and Circadian Rhythms Including Translational Approaches Collection.

The research of JM Krueger and colleagues, focusing on sleep organization as a means to elucidate sleep function, led to critical insights as to why we sleep. Krueger posited that, fundamentally, sleep occurs locally at the level of neuronal/glial assemblies (small networks of neurons and glia) and that the expression of sleep in these assemblies is dependent on their prior use. Neuronal/glial assemblies serve as units of information processing, which consumes energy and increases entropy so that the energy available for further information processing is use-dependently depleted. According to the laws of physics, when energy drops to a lower bound relative to entropy, information processing ceases - which results in local quiescence and locally reduced consciousness and manifests as use-dependent local sleep. The physics-based nature of local sleep implies that it is inevitable, has neither function nor purpose, and is by itself not subject to biology-based evolutionary shaping. But uncontrolled local sleep compromises vigilance and is a threat to safety, which needs to be addressed to ensure survival. This can be accomplished by preemptively regulating sleep at a more global level and in a way that is adapted to the organism's temporal, environmental and ecological niche. Such global sleep allows for energy resupply (through biological processes not unique to sleep) across many neuronal/glial assemblies simultaneously while the organism is relatively safe. Thus, global sleep regulation could be the biology-based adaptation to the physics-based problem of use-dependent local sleep intrusions into wakefulness. Global sleep precludes niche exploitation and thus comes at an opportunity cost - but, unlike local sleep, the regulation of global sleep is subject to evolutionary shaping and amenable to species-specific optimization. Furthermore, a variety of ancillary functions may be served during global sleep to retroactively address biological needs that arose from prior wakefulness. However, serving these functions may be merely opportunistic, as the temporal dynamics of global sleep regulation appear to be proactive rather than retroactive, prioritizing alignment of global sleep and wake timing with the organism's ecological niche. Regardless, the costs of use-dependent local sleep and the management thereof through global sleep regulation are likely to be outweighed by the evolutionary benefit of the presumed source of the local sleep problem - that is, information processing capability, or cognition. In essence, therefore, sleep may just be the unavoidable, but worthwhile, price we pay for cognition.