Effectiveness of caffeine and blue-enriched light on cognitive performance and electroencephalography correlates of alertness in a spaceflight robotics simulation.

Human cognitive impairment associated with sleep loss, circadian misalignment and work overload is a major concern in any high stress occupation but has potentially catastrophic consequences during spaceflight human robotic interactions. Two safe, wake-promoting countermeasures, caffeine and blue-enriched white light have been studied on Earth and are available on the International Space Station. We therefore conducted a randomized, placebo-controlled, cross-over trial examining the impact of regularly timed low-dose caffeine (0.3 mg per kg per h) and moderate illuminance blue-enriched white light (~90 lux, ~88 melEDI lux, 6300 K) as countermeasures, separately and combined, in a multi-night simulation of sleep-wake shifts experienced during spaceflight among 16 participants (7 F, ages 26-55). We find that chronic administration of low-dose caffeine improves subjective and objective correlates of alertness and performance during an overnight work schedule involving chronic sleep loss and circadian misalignment, although we also find that caffeine disrupts subsequent sleep. We further find that 90 lux of blue-enriched light moderately reduces electroencephalogram (EEG) power in the theta and delta regions, which are associated with sleepiness. These findings support the use of low-dose caffeine and potentially blue-enriched white light to enhance alertness and performance among astronauts and shiftworking populations.

Effects of caffeine and blue-enriched light on spare visual attention during simulated space teleoperation.

Safe and successful operation of the International Space Station robotic arm is a complex task requiring difficult bimanual hand coordination and spatial reasoning skills, adherence to operating procedures and rules, and systems knowledge. These task attributes are all potentially affected by chronic sleep loss and circadian misalignment. In a randomized, placebo-controlled, cross-over trial examining the impact of regularly timed low-dose caffeine (0.3 mg kg-1 h-1) and moderate illuminance blue-enriched white light (~90 lux, ~88 melEDI lux, 6300 K), 16 participants performed 3 types of realistic robotic arm tasks using a high-fidelity desktop simulator overnight. Our goal was to determine how these countermeasures, separately and combined, impacted telerobotic task performance and the ability to allocate attention to an unrelated secondary visual task. We found that all participants maintained a similar level of robotic task performance throughout the primary task but the application of caffeine separately and with blue-enriched light significantly decreased response time to a secondary visual task by -9% to -13%, whereas blue-enriched light alone changed average response times between -4% and +2%. We conclude that, for sleep-restricted individuals, caffeine improved their ability to divide their visual attention, while the effect of blue-enriched light alone was limited. Light and caffeine together was most effective. Use of these countermeasures should improve the margin of safety if astronauts perform familiar tasks under degraded conditions or novel tasks where task workload is increased.

Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans.

The PERIOD2 (PER2) gene is a core molecular component of the circadian clock and plays an important role in the generation and maintenance of daily rhythms. Rs35333999, a missense variant of PER2 common in European populations, has been shown to associate with later chronotype. Chronotype relates to the timing of biological and behavioral activities, including when we sleep, eat, and exercise, and later chronotype is associated with longer intrinsic circadian period (cycle length), a fundamental property of the circadian system. Thus, we tested whether this PER2 variant was associated with circadian period and found significant associations with longer intrinsic circadian period as measured under forced desynchrony protocols, the 'gold standard' for intrinsic circadian period assessment. Minor allele (T) carriers exhibited significantly longer circadian periods when determinations were based on either core body temperature or plasma melatonin measurements, as compared to non-carriers (by 12 and 11 min, respectively; accounting for ~7% of inter-individual variance). These findings provide a possible underlying biological mechanism for inter-individual differences in chronotype, and support the central role of PER2 in the human circadian timing system.

Increased vulnerability to attentional failure during acute sleep deprivation in women depends on menstrual phase.

Study Objectives: To investigate sex differences in the effect of sleep deprivation on performance, accounting for menstrual phase in women. Methods: We examined alertness data from 124 healthy women and men (40 women, 84 men; aged 18-30 years) who maintained wakefulness for at least 30 hr in a laboratory setting using a constant routine protocol. Objective alertness was assessed every 2 hr using a 10 min psychomotor vigilance task. Subjective alertness was assessed every hour via the Karolinska Sleepiness Scale. Results: Women in the follicular phase of the menstrual cycle demonstrated the poorest level of performance. This poor performance was most pronounced at times corresponding to the typical sleep episode, demonstrating a window of vulnerability at night during this menstrual phase. At 24 hr awake, over 60 per cent of their responses were lapses of >500 ms and over one-third of their responses were longer lapses of at least 3 s in duration. Women in the luteal phase, however, were relatively protected from alertness failure, performing similar or better than both follicular-phase women and men. Conclusions: These results have important implications for education and intervention programs for shift workers, specifically during times of vulnerability to attentional failure that increase risk of injury.

Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.

The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.

The progression of circadian phase during light exposure in animals and humans.

Studies in humans and mice revealed that circadian phase shifting effects of light are larger at the beginning of a light exposure interval than during subsequent exposure. Little is known about the dynamics of this response reduction phenomenon. Here the authors propose a method to obtain information on the progression of phase during light exposure. Phase response curves to intervals of light exposure over a wide range in duration are available for flesh flies, mice, and humans. By comparing the phase shifts induced by pulses of various durations but starting at the same circadian phase, the progression of phase during a long interval (hours) of light exposure is reconstructed for each of these 3 species. For flies, the phase progression curves show that light pulses-if long enough- eventually make the pacemaker stabilize around InT18 (near subjective dusk), as is typical for strong resetting. The progression of phase toward the final value never shows advances larger than 7 h, while delays can be as large as 18 h. By applying the phase progression curve method presented in this study, differences between advances and delays in type-0 phase response curves can be distinguished clearly. In flesh flies (Sarcophaga) this bifurcation between delays and advance occurs when light exposure starts at InT0 (subjective midnight). The present study confirms earlier findings in mice showing that the beginning of the light pulse generates stronger phase shifts than subsequent hours of light. Response reduction is complete within 1 h of exposure. It is argued that the variation is not so much due to light adaptation processes, but rather to response saturation. In contrast to light adaptation, response saturation is fundamental to proper functioning of the circadian pacemaker during natural entrainment. For understanding entrainment of the pacemaker to natural light, phase progression curves in which naturalistic light profiles are applied could be an important tool.

Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes.

CONTEXT: There is evidence of both hypothalamic-pituitary-adrenocortical (HPA) axis and cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the exact nature and the associations between these abnormalities remain unclear. OBJECTIVES: The aim of the study was to characterize the nature of the HPA dysregulation in T2DM and ascertain whether impaired cognition in T2DM could be attributed to these abnormalities. DESIGN: A cross-sectional study was performed, contrasting matched groups on HPA axis function and cognition by using the combined dexamethasone (DEX)/CRH test and a neuropsychological battery assessing declarative and working memory, attention, and executive function. SETTING: The study was conducted in a research clinic in an academic medical center. PARTICIPANTS: Participants were volunteers functioning in the cognitively normal range. We studied 30 middle-aged individuals with T2DM, on average 7.5 yr since diabetes diagnosis, and 30 age-, gender-, and education-matched controls. MAIN OUTCOME MEASURES: Basal cortisol levels, cortisol levels during the DEX/CRH test, and performance on neuropsychological tests were measured. RESULTS: Individuals with T2DM had elevated basal plasma cortisol levels, higher levels after DEX suppression, and a larger response to CRH (all P