Nocturnal hypoglycemia is associated with next day cognitive performance in adults with type 1 diabetes: Pilot data from the GluCog study.

OBJECTIVE:  Individuals with type 1 diabetes (T1D) have increased risk for cognitive dysfunction and high rates of sleep disturbance. Despite associations between glycemia and cognitive performance using cross-sectional and experimental methods few studies have evaluated this relationship in a naturalistic setting, or the impact of nocturnal versus daytime hypoglycemia. Ecological Momentary Assessment (EMA) may provide insight into the dynamic associations between cognition, affective, and physiological states. The current study couples EMA data with continuous glucose monitoring (CGM) to examine the within-person impact of nocturnal glycemia on next day cognitive performance in adults with T1D. Due to high rates of sleep disturbance and emotional distress in people with T1D, the potential impacts of sleep characteristics and negative affect were also evaluated. METHODS:  This pilot study utilized EMA in 18 adults with T1D to examine the impact of glycemic excursions, measured using CGM, on cognitive performance, measured via mobile cognitive assessment using the TestMyBrain platform. Multilevel modeling was used to test the within-person effects of nocturnal hypoglycemia and hyperglycemia on next day cognition. RESULTS:  Results indicated that increases in nocturnal hypoglycemia were associated with slower next day processing speed. This association was not significantly attenuated by negative affect, sleepiness, or sleep quality. CONCLUSIONS:  These results, while preliminary due to small sample size, showcase the power of intensive longitudinal designs using ambulatory cognitive assessment to uncover novel determinants of cognitive fluctuation in real world settings, an approach that may be utilized in other populations. Findings suggest reducing nocturnal hypoglycemia may improve cognition in adults with T1D.

Sleep and Pain in Veterans with Chronic Pain: Effects of Psychological Pain Treatment and Temporal Associations.

Introduction: Chronic pain is highly prevalent in US military Veterans. Non-opioid and non-pharmacologic treatments are recommended when clinically appropriate, but research on the mechanisms underlying benefits of these treatments is lacking. Here, we examined the role of sleep in the effects of three non-pharmacologic pain treatments in Veterans. Specifically, we investigated whether treatment effects on sleep predicted treatment effects on pain occurring later, or vice versa. Methods: Veterans enrolled in a randomized controlled trial were invited to participate in this supplementary sleep study. A total of 174 Veterans were randomized to one of three 8-session, in-person, group-based pain treatments: hypnosis, mindfulness meditation, or education control. Measurements included self-reported sleep disturbance, pain intensity, and pain catastrophizing; sleep duration was assessed with actigraphy. Sleep and pain measurements were obtained at baseline, posttreatment, and 3-month posttreatment follow-up. Results: At baseline, average pain intensity was moderate (mean ± SD: 5.7 ± 1.7 on the 0-10 Numeric Rating Scale), pain catastrophizing was just below the clinically relevant threshold (mean ± SD: 28.6 ± 12.2 on the Pain Catastrophizing Scale), and subjective sleep disturbance exceeded the US population average (mean ± SD: 58.5 ± 8.1 on the Patient Reported Outcomes Measurement Information System Sleep Disturbance - Short Form). By contrast, objective sleep duration was consistent with the recommended daily sleep amount of 7-8 h for adults (mean ± SD: 8.3 ± 1.4 h). Across treatment conditions, pain intensity, pain catastrophizing, and subjective sleep disturbance were significantly less at posttreatment and 3-month follow-up than at baseline (p < 0.001). Actigraphic sleep duration did not differ significantly as a function of time. There was a high degree of covariation among the measures of pain intensity, pain catastrophizing, and sleep disturbance (p < 0.05). However, self-reported sleep disturbance was not significantly correlated with actigraphic sleep duration (|r| <= 0.13, p > 0.05). Sleep and pain variables observed at prior assessments predicted these same variables at subsequent assessments. There was no significant evidence that changes in pain preceded changes in sleep or that changes in sleep preceded changes in pain (all p > 0.05). Discussion: For this study's Veterans, treatment-related changes in sleep and pain appeared to occur in parallel. The concomitant changes in sleep and pain suggest that therapies improving pain in Veterans may yield attendant benefits for the treatment of sleep, and possibly vice versa.

Nighttime Sleep and Respiratory Disturbances in Individuals Receiving Methadone to Treat Opioid Use Disorder.

ABSTRACT: Opioids are a leading cause of drug overdose deaths in the United States. Methadone used as medication for opioid use disorder (MOUD) reduces drug cravings and promotes abstinence. However, individuals in methadone-based MOUD treatment commonly report subjective sleep complaints and are at risk for respiratory depression from opioids. We investigated nighttime sleep and respiratory function in eight individuals (six women, two men; ages 31-68 years) in their first 90 days of methadone-based MOUD treatment. Participants underwent overnight cardiorespiratory polysomnography. Sleep and respiratory variables were characterized with descriptive statistics for comparison to reference data from similarly aged healthy adults. Although participants spent 8.1 ± 0.3 hours (mean ± SD ) in bed, their total sleep time was only 6.8 ± 1.3 hours. They exhibited longer sleep latency and intermittent wakefulness. Sleep structure was irregular, with disrupted sleep cycles. Participants also displayed a decreased amount of N1 sleep and an increased amount of N3 sleep, compared with reference data. Participants showed respiratory depression, with an average apnea-hypopnea index of 16.5 ± 8.9 events per hour. Central sleep apneas comprised 69.1% ± 20.9% of the respiratory events. A Cheyne-Stokes-like breathing pattern, consisting of 30-second cycles of three central sleep apneas, was observed in 75% of participants. Our results suggest that individuals early in methadone-based MOUD treatment experience disordered sleep and respiratory disturbances. Such nighttime physiological changes may have serious long-term health consequences and contribute to unintended overdose rates. Identifying and treating MOUD individuals with sleep apnea could reduce risk of death.

Race/ethnicity, sleep duration, and mortality risk in the United States.

Current evidence and professional guidance recommend sleeping between 7 and 9 h in a 24-h period for optimal health. The present study examines the association between sleep duration and mortality and assesses whether this association varies by racial/ethnic identity for a large and diverse sample of United States adults. We use data on 274,836 adults, aged 25 and older, from the 2004-2014 waves of the National Health Interview Survey (NHIS) linked to prospective mortality through 2015 (23,382 deaths). Cox proportional hazards models were used in multi-variable regressions to estimate hazard ratios for mortality by sleep duration and racial/ethnic identity, controlling for sociodemographic, socioeconomic, and psychological distress variables. We find elevated risks of mortality from any cause for adults who sleep less than 5 h or more than 9 h in a 24-h period after all adjustments. Further, we find evidence that these elevated risks for mortality are more pronounced for some racial/ethnic groups and less pronounced for others. Improved understanding of differences in sleep duration and sleep health can facilitate more effective and culturally-tailored interventions around sleep health, improving overall well-being and enhancing longevity.

Enhancing learning and retention through the distribution of practice repetitions across multiple sessions.

The acquisition and retention of knowledge is affected by a multitude of factors including amount of practice, elapsed time since practice occurred, and the temporal distribution of practice. The third factor, temporal distribution of practice, is at the heart of research on the spacing effect. This research has consistently shown that separating practice repetitions by a delay slows acquisition but enhances retention. The current study addresses an empirical gap in the spacing effects literature. Namely, how does the allocation of a fixed number of practice repetitions among multiple sessions impact learning and retention? To address this question, we examined participants' acquisition and retention of declarative knowledge given different study schedules in which the number of practice repetitions increased, decreased, or remained constant across multiple acquisition sessions. The primary result was that retention depended strongly on the total number of sessions in which an item appeared, but not on how practice repetitions were distributed among those sessions. This outcome was consistent with predictions from a computational cognitive model of skill acquisition and retention called the Predictive Performance Equation (PPE). The success of the model in accounting for the patterns of performance across a large set of study schedules suggests that it can be used to tame the complexity of the design space and to identify schedules to enhance knowledge acquisition and retention.

Effects of total sleep deprivation on components of top-down attentional control using a flexible attentional control task.

Sleep deprivation consistently decreases vigilant attention, which can lead to difficulty in performing a variety of cognitive tasks. However, sleep-deprived individuals may be able to compensate for degraded vigilant attention by means of top-down attentional control. We employed a novel task to measure the degree to which individuals overcome impairments in vigilant attention by using top-down attentional control, the Flexible Attentional Control Task (FACT). The FACT is a two-choice task that has trials with valid, invalid, and neutral cues, along with an unexpected switch in the probability of cue validity about halfway in the task. The task provides indices that isolate performance components reflecting vigilant attention and top-down attentional control. Twelve healthy young adults completed an in-laboratory study. After a baseline day, the subjects underwent 39 hours of total sleep deprivation (TSD), followed by a recovery day. The FACT was administered at 03:00, 11:00, and 19:00 during sleep deprivation (TSD condition) and at 11:00 and 19:00 after baseline sleep and at 11:00 after recovery sleep (rested condition). When rested, the subjects demonstrated both facilitation and interference effects on cued trials. While sleep deprived, the subjects showed vigilant attention deficits on neutral cue trials, and an impaired ability to reduce these deficits by using predictive contextual cues. Our results indicate that the FACT can dissociate vigilant attention from top-down attentional control. Furthermore, they show that during sleep deprivation, contextual cues help individuals to compensate partially for impairments in vigilant attention, but the effectiveness of top-down attentional control is diminished.

Sleep deprivation impairs binding of information with its context.

Binding information to its context in long-term memory is critical for many tasks, including memory tasks and decision making. Failure to associate information to its context could be an important aspect of sleep deprivation effects on cognition, but little is known about binding problems from being sleep-deprived at the time of encoding. We studied how sleep deprivation affects binding using a well-established paradigm testing the ability to remember auditorily presented words (items) and their speakers (source context). In a laboratory study, 68 healthy young adults were randomly assigned to total sleep deprivation or a well-rested control condition. Participants completed an affective item and source memory task twice: once after 7-hour awake during baseline and again 24 hours later, after nearly 31 hours awake in the total sleep deprivation condition or 7 hours awake in the control condition. Participants listened to negative, positive, and neutral words presented by a male or female speaker and were immediately tested for recognition of the words and their respective speakers. Recognition of items declined during sleep deprivation, but even when items were recognized accurately, recognition of their associated sources also declined. Negative items were less bound with their sources than positive or neutral items, but sleep deprivation did not significantly affect this pattern. Our findings indicate that learning while sleep-deprived disrupts the binding of information to its context independent of item valence. Such binding failures may contribute to sleep deprivation effects on tasks requiring the ability to bind new information together in memory.

Sleep Deprivation and Sleep-Onset Insomnia are Associated with Blunted Physiological Reactivity to Stressors.

INTRODUCTION: Military operations often involve intense exposure to stressors combined with acute sleep deprivation, while military personnel also experience high prevalence of chronic sleep deficiency from insomnia and other sleep disorders. However, the impact of acute and chronic sleep deficiency on physiologic stressor responses is poorly understood. In a controlled laboratory study with normal sleepers and individuals with chronic sleep-onset insomnia, we measured responses to an acute stressor administered in a sleep deprivation condition or a control condition. METHODS: Twenty-two adults (aged 22-40 years; 16 females)-11 healthy normal sleepers and 11 individuals with sleep-onset insomnia-completed a 5-day (4-night) in-laboratory study. After an adaptation day and a baseline day, subjects were assigned to a 38-hour total sleep deprivation (TSD) condition or a control condition; the study ended with a recovery day. At 8:00 PM after 36 hours awake in the sleep deprivation condition or 12 hours awake in the control condition, subjects underwent a Maastricht Acute Stress Test (MAST). Salivary cortisol was measured immediately before the MAST at 8:00 PM, every 15 minutes after the MAST from 8:15 PM until 9:15 PM, and 30 minutes later at 9:45 PM. Baseline salivary cortisol was collected in the evening of the baseline day. Additionally, before and immediately upon completion of the MAST, self-report ratings of affect and pain were collected. RESULTS: The MAST elicited a stressor response in both normal sleepers and individuals with sleep-onset insomnia, regardless of the condition, as evidenced by increases in negative affect and pain ratings. Relative to baseline, cortisol levels increased immediately following the MAST, peaked 30 minutes later, and then gradually returned to pre-MAST levels. At the cortisol peak, there was a significant difference across groups and conditions, reflecting a pronounced blunting of the cortisol response in the normal sleepers in the TSD condition and the sleep-onset insomnia group in both the TSD and control conditions. CONCLUSIONS: Blunted stressor reactivity as a result of sleep deficiency, whether acute or chronic, may reflect reduced resiliency attributable to allostatic load and may put warfighters at increased risk in high-stakes, rapid response scenarios.

Circulating Exosomal miRNAs Signal Circadian Misalignment to Peripheral Metabolic Tissues.

Night shift work increases risk of metabolic disorders, particularly obesity and insulin resistance. While the underlying mechanisms are unknown, evidence points to misalignment of peripheral oscillators causing metabolic disturbances. A pathway conveying such misalignment may involve exosome-based intercellular communication. Fourteen volunteers were assigned to a simulated day shift (DS) or night shift (NS) condition. After 3 days on the simulated shift schedule, blood samples were collected during a 24-h constant routine protocol. Exosomes were isolated from the plasma samples from each of the blood draws. Exosomes were added to naïve differentiated adipocytes, and insulin-induced pAkt/Akt expression changes were assessed. ChIP-Seq analyses for BMAL1 protein, mRNA microarrays and exosomal miRNA arrays combined with bioinformatics and functional effects of agomirs and antagomirs targeting miRNAs in NS and DS exosomal cargo were examined. Human adipocytes treated with exosomes from the NS condition showed altered Akt phosphorylation responses to insulin in comparison to those treated with exosomes from the DS condition. BMAL1 ChIP-Seq of exosome-treated adipocytes showed 42,037 binding sites in the DS condition and 5538 sites in the NS condition, with a large proportion of BMAL1 targets including genes encoding for metabolic regulators. A significant and restricted miRNA exosomal signature emerged after exposure to the NS condition. Among the exosomal miRNAs regulated differentially after 3 days of simulated NS versus DS, proof-of-concept validation of circadian misalignment signaling was demonstrated with hsa-mir-3614-5p. Exosomes from the NS condition markedly altered expression of key genes related to circadian rhythm in several cultured cell types, including adipocytes, myocytes, and hepatocytes, along with significant changes in 29 genes and downstream gene network interactions. Our results indicate that a simulated NS schedule leads to changes in exosomal cargo in the circulation. These changes promote reduction of insulin sensitivity of adipocytes in vitro and alter the expression of core clock genes in peripheral tissues. Circulating exosomal miRNAs may play an important role in metabolic dysfunction in NS workers by serving as messengers of circadian misalignment to peripheral tissues.

TNFα G308A genotype, resilience to sleep deprivation, and the effect of caffeine on psychomotor vigilance performance in a randomized, double-blind, placebo-controlled, crossover study.

The TNFα G308A gene polymorphism has been reported to influence performance impairment during total sleep deprivation (TSD). We investigated this effect in a randomized, double-blind, crossover laboratory study of repeated exposure to 48 h TSD with caffeine administration at different doses. In a retrospective analysis, we replicated the finding that the A allele of TNFα G308A, found in 4 of 12 study participants, confers resilience to performance impairment during TSD. There was no evidence of an interaction of TNFα genotype with the beneficial effect of caffeine (200 or 300 mg) on performance during TSD, suggesting distinct underlying mechanisms.

Robustness of inter-individual differences in slow wave sleep for daytime sleep periods after total sleep deprivation with or without caffeine administration: potential implications for around-the-clock operations.

There are large inter-individual differences in slow wave sleep, which constitute a trait or phenotype. We investigated whether the manifestation of this trait is impacted by daytime sleeping after sleep deprivation, and to what extent it is robust to prior caffeine intake. N = 12 subjects underwent three 48 h periods of total sleep deprivation with different caffeine dosing regimens. There were significant, considerable, and robust inter-individual differences in slow wave sleep across nighttime sleep opportunities before, and daytime sleep after, total sleep deprivation, regardless of caffeine dosing. The robustness of this phenotype may have functional implications for individuals in around-the-clock operational settings.

Speed/accuracy trade-off in the effects of acute total sleep deprivation on a sustained attention and response inhibition task.

Total sleep deprivation (TSD) is known to impair sustained attention. However, previously reported effects of TSD on response inhibition are mixed. We administered a "stop-signal" variation of the psychomotor vigilance test, which included 25% of trials requiring withholding of a response to assess response inhibition alongside sustained attention. Participants completed the task at baseline and after 34.5 h of wakefulness. Accuracy was not reduced during TSD. However, response times were significantly slower. A speed/accuracy trade-off allowed participants to effectively withhold responses on inhibition trials and conferred resilience of inhibitory control during TSD under conditions of relatively low time pressure.

Action plan interrupted: resolution of proactive interference while coordinating execution of multiple action plans during sleep deprivation.

The ability to retain an action plan to execute another is necessary for most complex, goal-directed behavior. Research shows that executing an action plan to an interrupting event can be delayed when it partly overlaps (vs. does not overlap) with the retained action plan. This phenomenon is known as partial repetition costs (PRCs). PRCs reflect proactive interference, which may be resolved by inhibitory, executive control processes. We investigated whether these inhibitory processes are compromised due to one night of sleep deprivation. Participants were randomized to a sleep-deprived group or a well-rested control group. All participants performed an action planning task at baseline after a full night of sleep, and again either after a night of sleep deprivation (sleep-deprived group) or a full night of sleep (control group). In this task, two visual events occurred in a sequence. Participants retained an action plan to the first event in working memory while executing a speeded action to the second (interrupting) event; afterwards, they executed the action to the first event. The two action plans either partly overlapped (required the same hand) or did not (required different hands). Results showed slower responses to the interrupting event during sleep deprivation compared to baseline and the control group. However, the magnitude of the PRCs was no different during sleep deprivation compared to baseline and the control group. Thus, one night of sleep deprivation slowed global responses to the interruption, but inhibitory processes involved in reducing proactive interference while responding to an interrupting event were not compromised. These findings are consistent with other studies that show sleep deprivation degrades global task performance, but does not necessarily degrade performance on isolated, executive control components of cognition. The possibility that our findings involve local as opposed to central inhibition is also discussed.

Psychomotor Vigilance Impairment During Total Sleep Deprivation Is Exacerbated in Sleep-Onset Insomnia.

PURPOSE: Individuals with primary insomnia frequently report cognitive impairment as a next-day consequence of disrupted sleep. Studies attempting to quantify daytime impairment objectively in individuals with insomnia have yielded mixed results, with evidence suggesting impairments in aspects of executive functioning but not psychomotor vigilance. It has been suggested that persons with insomnia may have latent performance deficits for which they would be able to compensate effectively under normal daytime circumstances - suggesting that any such deficits may be exposed through perturbation. In this context, we used a laboratory-based total sleep deprivation (TSD) paradigm to investigate psychomotor vigilance performance in individuals with chronic sleep-onset insomnia as compared to healthy normal controls. PARTICIPANTS AND METHODS: Fourteen participants, seven individuals with chronic sleep-onset insomnia (ages 24-40y) and seven age-matched, healthy normal sleepers completed a highly controlled in-laboratory study involving 38 h of TSD. A 10 min and a 3 min version of the psychomotor vigilance test (PVT) were administered every 3 h during TSD. RESULTS: In both the individuals with sleep-onset insomnia and the age-matched normal sleepers, lapses of attention and false starts on the PVT were relatively infrequent during the first 16 h of the TSD period, but increased significantly when wakefulness was extended beyond 16 h. However, the effects of TSD on PVT performance were considerably exacerbated in the sleep-onset insomnia group, which showed about twice as many lapses of attention, more than twice as many false starts, and approximately twice as big a time-on-task effect on the 10 min PVT as the age-matched normal sleepers group, with similar findings on the 3 min PVT. CONCLUSION: These findings indicate that daytime impairment reported by individuals with sleep-onset insomnia has an objective performance component that is exposed during TSD. Thus, persons with sleep-onset insomnia could be at increased risk of performance impairment in settings that involve extended wakefulness. This underscores the importance of treating insomnia and suggests that laboratory sleep deprivation studies could serve to document the effectiveness of treatment approaches.

Cardiac autonomic activity during sleep deprivation with and without caffeine administration.

Caffeine is often consumed to mitigate degraded alertness associated with sleep deprivation. Both caffeine and sleep deprivation have been implicated in cardiovascular disease, but evidence is largely anecdotal. We determined the effects of sleep deprivation and caffeine on markers of cardiac autonomic activity. Twelve healthy young adults completed an 18-day laboratory study. They were exposed to three 48 h sessions of acute total sleep deprivation (TSD), each separated by three recovery days. In randomized, counter-balanced order, subjects received 0 mg (placebo), 200 mg, or 300 mg of caffeine at 12 h intervals during each sleep deprivation session. Every 2 h during scheduled wakefulness, a 15-minute neurobehavioral task battery was administered, during which heart rate (HR) and the high frequency (HF) component of the HR variability power spectrum (HF-HRV) were measured. Caffeine administration decreased HR and increased HF-HRV, indicating elevated parasympathetic activity. The 300 mg caffeine dose did not significantly affect autonomic activity to a greater extent than the 200 mg dose. There was no significant effect of 48 h of TSD on HR, whereas there was a small increase across hours awake in HF-HRV. There was no significant interaction of TSD with caffeine. Circadian rhythmicity in HR and HF-HRV surpassed the magnitude of the effects of caffeine and TSD. Caffeine and acute TSD thus produced only modest changes in cardiac autonomic activity, unlikely to have immediate clinical implications in healthy young adults. However, further research is needed to determine the long-term effects of chronic exposure to sleep loss and/or caffeine on cardiac health, and to determine the generalizability of our findings to non-healthy populations.

Randomized, double-blind, placebo-controlled, crossover study of the effects of repeated-dose caffeine on neurobehavioral performance during 48 h of total sleep deprivation.

RATIONALE: Caffeine is widely used as a countermeasure against neurobehavioral impairment during sleep deprivation. However, little is known about the pharmacodynamic profile of caffeine administered repeatedly during total sleep deprivation. OBJECTIVES: To investigate the effects of repeated caffeine dosing on neurobehavioral performance during sleep deprivation, we conducted a laboratory-based, randomized, double-blind, placebo-controlled, crossover, multi-dose study of repeated caffeine administration during 48 h of sleep deprivation. Twelve healthy adults (mean age 27.4 years, six women) completed an 18-consecutive-day in-laboratory study consisting of three 48 h total sleep deprivation periods separated by 3-day recovery periods. During each sleep deprivation period, subjects were awakened at 07:00 and administered caffeine gum (0, 200, or 300 mg) at 6, 18, 30, and 42 h of wakefulness. The Psychomotor Vigilance Test and Karolinska Sleepiness Scale were administered every 2 h. RESULTS: The 200 and 300 mg doses of caffeine mitigated neurobehavioral impairment across the sleep deprivation period, approaching two-fold performance improvements relative to placebo immediately after the nighttime gum administrations. No substantive differences were noted between the 200 mg and 300 mg caffeine doses, and adverse effects were minimal. CONCLUSIONS: The neurobehavioral effects of repeated caffeine dosing during sleep deprivation were most evident during the circadian alertness trough (i.e., at night). The difference between the 200 mg and 300 mg doses, in terms of the mitigation of performance impairment, was small. Neither caffeine dose fully restored performance to well-rested levels. These findings inform the development of biomathematical models that more accurately account for the time of day and sleep pressure-dependent effects of caffeine on neurobehavioral performance during sleep loss.